Open Positions

This is the list of the group leaders working in the institutes of the SEMM network, who have open positions.
The number and project descriptions can vary during the application period.

Use the filter below to browse the different projects:

Surname Name Research center/University Research Areas N. of positions Proposed PhD Project
Amati Bruno
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European Institute of Oncology (IEO) Molecular and Cellular Biology, Molecular Oncology, Omics Sciences (genomics and other omics) 2
Unraveling oncogene-induced dependencies in MYC-driven tumors: molecular mechanisms and therapeutic development

The oncogenic transcription factor MYC is induced by growth-promoting stimuli and drives the activation of biosynthetic and metabolic pathways inherent to proliferating cells. The same pathways are deregulated in MYC-driven tumors where they contribute to cell proliferation and survival, but concomitantly elicit multiple stresses, to which cancer cells must adapt during disease progression. Hence, MYC-overexpressing cells depend on a fragile equilibrium between conflicting signals, which creates opportunities to exploit synthetic lethality as a strategy for targeted therapeutic intervention.  
Our projects build upon this concept, following from the discovery of new genetic and pharmacological dependencies in MYC-driven lymphomas. We will pursue in-depth characterization of the mechanisms underlying these pharmacogenetic interactions, at the cellular, molecular and genomic levels. In turn, the new mechanistic insight shall allow us to unravel innovative intervention principles, combinatorial drug interactions and therapeutic opportunities. 

Bachi Angela
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IFOM ETS - The AIRC Institute of Molecular Oncology Cancer Metabolism, Molecular and Cellular Biology, Omics Sciences (genomics and other omics) 1
BACE2 shapes tumor microenvironment

We have recently discovered that BACE2-dependent amyloid fibrils are new components of the tumor extracellular environment in metastatic melanoma where they promote cell proliferation through the activation of the transcriptional coactivator YAP, a master sensor of extracellular stiffness (Matafora V et al. Amyloid aggregates accumulate in melanoma metastasis modulating YAP activity. 2020, EMBO Rep).
We have also noticed that the protease BACE2 is overexpressed in several solid tumors (Farris F et al. The emerging role of β-secretases in cancer. J EXP CLIN CANC RES 2021) raising the intriguing hypothesis that it could actively take part in tumor biology.
Moreover, recent data of the lab demonstrate that BACE2 has an active role in lipid metabolism homeostasis.
Aim of this project will be the elucidation of the role of BACE2 in shaping tumor microenvironment. In particular, the student will be involved in the development of highly sensitive proteomics and metabolomics methods able to dissect the proteome and lipidome complexity up to single cell resolution by using cutting-edge imaging and mass spectrometric techniques.

Bardelli Alberto
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University of Turin Molecular and Cellular Biology, Molecular Oncology, Omics Sciences (genomics and other omics) 1
Biological and molecular characterization of colorectal cancers

Colorectal cancer (CRC) is among the leading malignancies worldwide. Although targeted therapies revolutionized the clinical treatment of cancer patients, presently chemotherapies remain the standard-of-care for many CRC patients. Administration of targeted therapies, based on the molecular characterization of patient disease, often leads to a significant clinical response and tumor shrinkage. However, even after potent tumor shrinkage the secondary resistance inevitably develops.
The candidate will employ genetic, pharmacological and functional screenings to shed more light on potentially actionable vulnerabilities of CRC cells, with the final aim to design novel therapeutic strategies to interfere with tumor plasticity, thus preventing the recurrence of the disease and prolonging the clinical benefit for cancer patients. To address this, the candidate will take advantage of a CRC bank of >260 2D cell lines and >50 patients-derive organoids (PDO), high-throughput technologies and computational methodologies to identify and characterize novel CRC features, targets and/or combinatorial strategies to prevent tumor plasticity and curb the development of drug-resistance. 
The research project will be carried out at the Department of Oncology of the University of Turin.

Bodega Beatrice
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National Institute of Molecular Genetics (INGM) Omics Sciences (genomics and other omics), Epigenetics, Immunology 1
Defining LINE1-transcript dynamics in tumor-infiltrating lymphocytes at single cell resolution

The composition of tumor-infiltrating lymphocytes (TILs) exhibits significant heterogeneity, particularly marked by a high proportion of exhausted TILs and Tregs that are correlated with poor prognosis. Despite the transformative impact of immune checkpoint inhibitors on cancer treatment, a significant portion of patients still don't respond to therapy. Thus, there's an urgent call to uncover fresh targets to improve treatment efficacy.
We have recently discovered that Long Interspersed Nuclear Elements 1 (LINE1) are spliced as novel exons in alternative transcript variants (LINE1-transcripts), resulting in the repression of genes crucial for cellular activation. Interestingly, these elements gather in exhausted TILs and their downregulation restore the effector functions of these cells. Therefore, our goal is to investigate the LINE1-transcript pattern within CD3+ TILs utilizing single-cell full-length short and long-read sequencing combined with de novo transcriptome reconstruction approaches. Subsequently, we plan to interfere with LINE1-transcript expression using CRISPR/Cas13 screening coupled with scRNA-sequencing to to pinpoint specific transcripts implicated in T-cell exhaustion. This project holds promise in uncovering fresh avenues for cancer immunotherapy.

Bonaldi Tiziana
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European Institute of Oncology (IEO) Epigenetics, Molecular Oncology, Omics Sciences (genomics and other omics), Molecular and Cellular Biology 1
MS-based proteomics and multi-omics to characterise the role of epigenetic enzymes in cancer heterogeneity, plasticity, and response to treatment

Within a multi-disciplinary AIRC project whereby MS-based profiling of protein modifications is coupled with epigenomics and transcriptomics, together with the pharmacological and genetic modulation of epigenetic enzymes and phenotypic cellular assays, the selected PhD student will contribute to the functional and mechanistic investigation of the role of protein methylation in ovarian cancer chemo-resistance, at the transcriptional, translational and metabolic level.

Branzei Dana
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IFOM ETS - The AIRC Institute of Molecular Oncology Molecular and Cellular Biology, Molecular Oncology 1
Identifying the functional and physical network of the cohesin loader Scc2/NIPBL in genome integrity

Using mass spectrometry and proximity ligation approaches we will identify the interactors and the physical environment of Scc2/NIPBL, sensitive to its ability to interact with PCNA via PIP motifs present in the C-terminus that we recently identified (Psakhye, Kawasumi et al, NSMB, 2023). The key targets will be validated and tested for their roles in affecting cohesion and DNA repair/recombination in either control and cohesin loader mutants. In a parallel approach, we will screen for mutants that severely aggravate the cohesion defects of the cohesin loader mutants defective in engaging in interaction with PCNA or rescue the synthetic defects arising when these mutants are combined with mutations in replisome factors providing for cohesion in compensatory manner.

Buffa Francesca
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IFOM ETS - The AIRC Institute of Molecular Oncology Computational Biology and Bioinformatics, Human Genetics and Genomics, Omics Sciences (genomics and other omics) 1
Adaptation to hypoxia and EMT

We will produce multi-omics data in bulk and single cells, in time series, to reconstruct the molecular pathways used during adaptation of cancer cells to a hypoxic TME. The project will involve both wet lab and computational techniques. The computational part will be done in collaboration with the AI team at Bocconi University.

Casañal Ana
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Human Technopole (HT) Structural biology 2
Molecular Mechanisms of RNA editing machines

Gene expression can be regulated at multiple levels. This allows organisms to respond fast to specific cellular stimuli while maintaining a stable internal environment. This regulation can be achieved through chemical marks on DNA, RNA and proteins.
The Casañal Group focuses on the study of RNA modifications, particularly within messenger RNA (mRNA). mRNA marks are involved in essential cellular roles, such as development and stress, and their deregulation is linked to human disorders, including cancer, infertility and depression. Despite their fundamental importance, chemical modifications on mRNA remain poorly understood in mechanistic terms. The Casañal Group uses and integrated structural biology approach, which combines cryo-EM and mass spectrometry with biochemical and biophysical methods, to understand the structure and function of the macromolecular machines that modify RNA. By understanding how these multi-protein complexes work within the cell, we will gain insight into how they regulate gene expression and how they impact various diseases. This, in turn, will help discover new therapeutic targets for drug development.
Our powerful multi-technique approach offers a unique advantage to succeed in challenging projects and allows our students to learn several state-of-the-art biochemical, biophysical and structural biology techniques. We are part of the Structural Biology Centre at Human Technopole, a new research institute designed from the ground up to facilitate cutting edge research that provides access to excellent infrastructure and core facilities.
We are looking for enthusiastic candidates intrigued by how proteins work, with a keen interest in structural methods and biological mechanisms, to join our interdisciplinary and international team.
For more information, visit https://humantechnopole.it/en/research-groups/casanal-group/.
For informal enquires contact ana.casanal[at]fht.org.

Chiocca Susanna
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European Institute of Oncology (IEO) Epigenetics 1
New markers in viral driven- head and neck cancer

Human papilloma virus (HPV) represents a strong prognostic factor for both improved survival and reduced risk of relapse of patients affected by oropharyngeal squamous cell carcinoma (OPSCC); however, there is a subset of HPV- positive OPSCC patients who still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse, are still lacking suitable prognostic biomarkers for clinical outcome prediction. Therefore, the identification of new prognostic molecular markers is urgently needed to more precisely identify OPSCC patients at higher risk of progression.

Coscia Francesca
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Human Technopole (HT) Structural biology 1
Integrative structural biology of thyroid hormone regulation in health and disease

Thyroid hormones are essential iodinated molecules produced by the thyroid gland and essential for the metabolism and growth of all vertebrates. In humans, thyroid hormone levels are finely tuned across life and development, and their unbalance is related to cancer, hypothyroidism, and autoimmune diseases.
What are the molecular determinants of thyroid hormone regulation?
The successful PhD candidate will reveal how thyroglobulin, the thyroid hormone precursor, orchestrates the hormone balance with its many partners. How? Using an integrative structural biology approach, ranging from in vitro biochemical and biophysical assays, cryo-EM analysis and structural proteomics, including crosslinking-mass spectrometry. The in vitro models built with high-resolution methods during the PhD project will be then tested in cells and potentially in organoid models. This study is essential to open new avenues towards the regulation of thyroid hormones in health and disease.
For more details on Francesca Coscia’s group and funding, please visit:
https://humantechnopole.it/en/research-groups/coscia-group/
https://erc.europa.eu/news/erc-starting-grants-2021-project-highlights

Costanzo Vincenzo
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IFOM ETS - The AIRC Institute of Molecular Oncology Molecular and Cellular Biology, Molecular Oncology 1
Mastering the Survival Secrets of Cancer: Unveiling and Targeting the Hidden Mechanisms Behind Cancer Therapy Resistance and Cellular Endurance

By combining biochemical analysis with advanced imaging techniques based on transmission electron microscopy (EM) we showed for the first time that stable RAD51 nucleofilament formation is directly required to prevent DNA degradation by MRE11 and other nucleases, and that extensive nascent DNA degradation leading to widespread mutagenesis can be triggered by the formation of reversed forks induced by SNF2 helicases (Kolinjivadi, 2017 Mol Cell; Taglialatela, 2017 Mol Cell). Our work has also revealed a role for BRCA2/RAD51 in preventing single stranded (ss) DNA gaps at replication forks (Kolinjivadi, 2017 Mol Cell; Taglialatela, 2021 Mol Cell). More recently, we have uncovered a novel function for PolQ in filling ssDNA gaps generated at replication forks in the absence of RAD51 and preventing MRE11-dependent replication fork breakage {Mann, 2022 Mol Cell; Schrempf 2022 Cell Reports).
We now propose to further dissect and exploit the compensatory mechanisms  that maintain fork integrity allowing cancer cell survival despite essential DNA repair genes impairment, spontaneous DNA damage accumulation and elevated levels of transcription.  The targeting of such mechanisms could lead to effective treatments of different types of tumors by synthetic lethality sparing normal cells. 

Costanzo Vincenzo
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IFOM ETS - The AIRC Institute of Molecular Oncology Computational Biology and Bioinformatics, Molecular Oncology, Omics Sciences (genomics and other omics) 1
Decoding the Mysteries of Cancer: Harnessing the Power of Genomics, Deep Learning, and Bioinformatics to Decipher the Complex Interplay of Protein Interactions and DNA Repair in Cancer Cells

In cancer, mutations disrupt protein networks, altering cell behavior to boost survival and therapy resistance. These changes rewire pathways and alter protein functions, allowing evasion from treatment and propagation. Such adaptation aids in withstanding stress, evading cell death, and sustaining malignancy, complicating treatment.
The goal of this project is to examine a diverse array of proprietary and public multidimensional biological data to decode the complex ties between protein interactions and gene mutations in cancer cells with defective DNA repair. The project will leverage the capabilities of AlphaFold Multimer to predict protein structures and interactions, providing a structural context to the genetic data.
Interaction networks will then be constructed to identify key proteins and pathways affected by mutations and discover novel associations using deep learning. 
Genomics and CRISPR-Cas9 based tools will be used to validate in silico prediction. 
This innovative approach has the potential to reveal how cancer cells maintain their survival and identify novel targets for cancer therapy.

d'Adda di Fagagna Fabrizio
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IFOM ETS - The AIRC Institute of Molecular Oncology Biology of Ageing, Molecular and Cellular Biology, Molecular Oncology 1
The role of DNA damage-induced non coding RNA in cancer and aging

We have a long-standing interest in DNA damage response (DDR) mechanisms in mammals and in the study of their impact on cellular senescence in the context of cancer and aging. We recently discovered that sites of DNA damage trigger the synthesis of non coding RNA that control DDR activation. Antisense oligonucleotides (ASO) against such ncRNA are site-specific DDR inhibitors. We are now exploiting this approach to study the contribution of DDR to the biology of cancer in cultured cells and in vivo, also in combination with novel pharmacological treatments, and to the biology of aging in cultured cells and in animal models of human diseases, with a specific interest on the impact telomere DNA damage and dysfunction.

d'Adda di Fagagna Fabrizio
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IFOM ETS - The AIRC Institute of Molecular Oncology Telomeres, Aging, Vaccines 1
Impact of telomere dysfunction on immune system deregulation

We recently demonstrated that we can improve the biology of the aging immune system with an innovative RNA-based therapy that targets telomere dysfunction. The candidate will explore the possibility that this approach can improve the immune response in transgenic and naturally-aged mice.

Davila-Velderrain Jose
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Human Technopole (HT) Computational Biology and Bioinformatics, Neurobiology, Omics Sciences (genomics and other omics) 1
Systems biology of glial cell evolution, aging, and rejuvenation

Most of the cells in our brain are not neurons. Neurons depend on different types of glial cells to function. Without glial cells, the nervous function of big animals will cease to exist due to bioenergetic, structural, and immunogenic constraints. Both neuronal and glial function is thus necessary for maintaining brain homeostasis, a task that becomes more and more challenging as we age. In this project we aim to combine computational models with comparative neurogenomic analyses across organisms, developmental time points, and pathological conditions to uncover principles underlying physiological dependencies between neuronal and glial cells. Disruption of these dependencies can offer new insights into the biological bases underlying the increased risk to neurodegeneration in aging and its potential reversal.

Davila-Velderrain Jose
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Human Technopole (HT) Computational Biology and Bioinformatics, Neurobiology, Omics Sciences (genomics and other omics) 1
Genomic basis of bioelectricity in evolution, development, and disease

Electricity is an important signaling modality that large animals (like us) use to rapidly modify their behavior in response to stimuli. Rapid electrical signaling is a multiscale process involving excitable organs, cells, and molecules. How nervous systems have acquired the ability to use electricity for rapid signaling across evolution and in development? And why can its disruption lead to neurological disease? In this project we will combine comparative genomics, comparative single-cell transcriptomics, mathematical modeling, and cellular electrophysiology to develop a better, multi-scale understanding of bioelectricity. Bioelectric signaling can be exploited for interventions addressing disorders of cellular collectives beyond the nervous system.

De Maria Ruggero
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Catholic University of the Sacred Heart Molecular Oncology, Omics Sciences (genomics and other omics) 1
Multiorgan Characterization of Colorectal Cancer Metastasis and Cancer Stem Cell Niches and the Impact on Immunotherapy

The overall goal of this proposal is to tackle some of the most crucial issues underlying the study of the biology of metastatic colorectal cancer (CRC) stem cells in different organs. This will be pursued with the main aims of deciphering cancer stem cell biology and understanding the influence of multiorgan niches on metastatic activity, with the aim of identifying prognostic biomarkers and developing innovative and more efficacious, patient-specific therapeutics for treatment. Colorectal tumors can present local, regional, and distant recurrences. Overall, relapses occur in 25% of operated patients. However, the majority of these patients present distant metastases, most commonly located in the liver (approximately 80%), followed by the lungs (approximately 25%) and peritoneum.
Taking advantage of our sophisticated orthotopic xenograft models in immunocompromised mice, we will compare the metastatic patient samples with the corresponding metastatic xenografts. Moreover, we will analyze the penetration, localization, and cytotoxic activity of adoptive CAR T cell delivery in these metastatic xenografts. The multi-omics characterization of this tumor will lead to the identification of metastasis-initiating cells, their microenvironment, and the interaction of CAR T cells in the metastatic niche. Together, this study will define the multiorgan niches for cancer stem cells while providing key information on the possible development of adoptive immunotherapy in metastatic CRC, thus helping better stratify patients for a more appropriate use of new emerging therapies.

Doksani Ylli
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IFOM ETS - The AIRC Institute of Molecular Oncology Biology of Ageing, Molecular and Cellular Biology, Molecular Oncology 1
Investigating telomere loss during replication

Telomere erosion plays important roles in cancer and ageing. Apart from the gradual shortening due to the loss of telomerase activity, telomeres are also lost because of replication failures. We study the molecular mechanisms of the replication stress response at mouse and human telomeres and its role in maintaining telomere integrity.
The project will require the generation of conditional mutants in key replication factors using CRISPR knock-in methods. These mutants will then be used for genetic analysis of telomere replication. The analysis will involve imaging of telomere structure in electron microscopy as well as monitoring replication of telomeres in DNA combing and 3rd generation sequencing. The student will make extensive use of molecular and cell biology techniques as well as acquiring expertise in the fields of telomere biology, DNA replication, DNA damage response, and genetics. 

Domínguez Conde Cecilia
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Human Technopole (HT) Immunology, Omics Sciences (genomics and other omics) 1
Assessing the allelic landscape of T cell deficiency and dysregulation

The first years of human life are key for shaping the adaptive immune system. On the one hand, we establish tolerance against self and environmental antigens while on the other hand we develop effector memory against pathogenic microorganisms. In certain genetic conditions, these processes become compromised with life-threatening consequences. Despite a strong association between specific alleles and immunodeficiency or immune dysregulation, the molecular consequences of these alleles remain poorly understood.

Recent developments in disease modeling offer unprecedented opportunities to deeply dissect these conditions. Specifically, we will use thymic organoids, genome engineering and single-cell multimodal techniques to obtain a molecular characterization of human cells spanning a diverse range of alleles. As part of this PhD project, the candidate will focus on 3 major goals:

1)    Ex vivo profiling of primary cells derived from patient blood and/or lymphoid tissues 
2)    Assessment of the effect of specific alleles on lymphocyte differentiation
3)    Reconstitution experiments using genome engineering to determine causality

By the end of this project, we expect to gain insights into the molecular mechanisms underlying T cell deficiency and dysregulation that will, in the long term, guide the design of targeted therapeutic strategies.

Erdmann Philipp Sebastian
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Human Technopole (HT) Structural biology 1
Organization of Neuronal Nucleoli In Situ

Nucleoli are one of the most important cellular organelles as they are responsible for ribosome biogenesis and hence protein homeostasis. In dividing cells, they regenerate during each cell cycle. Neurons, on the other hand, are post-mitotic and have adapted to this lifestyle also in terms of their nucleolar organization, shape, and number.
We here seek to resolve the structure of neuronal nucleoli in human by cryo-electron tomography and expansion microscopy, to answer how their specific adaptations make them more fit to fulfill functions in these highly specialized cells, and investigate how their organization is disrupted in neurodegenerative disorders.

Gauthier Nils
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IFOM ETS - The AIRC Institute of Molecular Oncology Molecular and Cellular Biology, Molecular Oncology, Mechanobiology 1
Mechanobiology of Glioblastoma

Glioblastoma (GBM) are very aggressive tumors (14 months of life expectancy after diagnosis). They are non-curable because GBM cells are highly proliferative and exceedingly invasive, migrating on linear tracks like the abluminal walls of brain blood vessels. Glioblastoma transcriptomic and genomic analysis showed high inter- and intra-patient heterogeneity. We also showed high inter-patient heterogeneity in GBM motility modes and linked them to their mechanoproperties. We proved the value of gridded micropatterns as a mimicry of peri-vascular migration. At this stage, we want to investigate more deeply GBM heterogeneity in motility modes, mechanoproperties and molecular signatures at single patient level.
Our idea is to identify, classify, and analyze the various motility modes present in clonal populations from single patients. Each mode will be tagged with a mechanical signature (stiffness, response to forces, capacity to generate forces…) and correlated with molecular signatures. This will define the mechanobiology landscape of GBMs and identify the most dangerous subpopulations. We will also study molecular players known to regulate migration and motility in the context of glioblastoma. 

Geginat Jens
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National Institute of Molecular Genetics (INGM) Computational Biology and Bioinformatics, Immunology, Omics Sciences (genomics and other omics) 1
Linking T-cell clonal expansions to TCR specificities in immune-mediated disease

T cells are key cellular players of the immune system. T-cell activation, proliferation and differentiation are controlled by the T cell receptor (TCR), a heterodimeric protein encoded by somatically diversified α and β loci. Clonally expanded T cells recognise the same antigens, i.e. MHC-peptide complexes, but may belong to different T lymphocytes subsets, depending on the type of immune response.
The aim of this project is to analyse the differentiation state of clonally expanded T-cells that recognise antigens which are associated with autoimmunity or cancer. These antigens include both self/tumor-antigens and disease-associated persistent viruses. In particular, Epstein Barr Virus-specific T-cells in multiple sclerosis or EBV-associated tumours will be a focus. To identify expanded TCR clonotypes recognising disease-associated antigens, we plan to combine single-cell RNA sequencing (scRNA-seq) data with TCR sequences of antigen-specific cells from the same individuals. Furthermore, the successful candidate is expected to exploit published datasets, including CITE-seq and ATAC-seq data. 

Harschnitz Oliver
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Human Technopole (HT) Developmental and Stem Cell Biology, Neurobiology 1
Development of a 3D assembloid model to study host-virus interactions in the human nervous system

Herpes simplex virus (HSV-1) is a common virus that in rare cases invades the central nervous system (CNS), causing a devastating and potentially lethal viral encephalitis. Despite antiviral therapy, encephalitis patients often suffer from severe neurological deficits. For many neurotropic viruses, including HSV-1, it is not fully understood which receptors enable viral entry, which host antiviral factors are crucial for CNS cell-intrinsic immunity, thus allowing for viral spread from the peripheral to the central nervous system.
Advancements in human pluripotent stem cell (hPSC) technology offer a unique opportunity to study host-virus interactions in human, disease relevant cells. This project will focus on the development of a novel hPSC-based organoid fusion model to study the molecular mechanisms underlying acute viral infection, the establishment of viral latency, and the temporal dynamics of viral spread of HSV-1 throughout different compartments of the human nervous system. Differentiation of hPSCs into region-specific organoids will be achieved through careful patterning using small molecules and morphogens and characterized by the use of hPSC reporter lines, high-resolution imaging, and single cell genomics. Subsequent tissue engineering will allow the fusion of multiple organoids to generate complex 3D-models to study host-virus interactions in a human, disease-relevant background.

Harschnitz Oliver
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Human Technopole (HT) Developmental and Stem Cell Biology, Neurobiology 1
Targeting ADA-SCID neuropathology in a patient-derived organoid platform

As the hallmark of adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID), immune system dysfunction is the cause of a life-threatening condition if not treated, due to a failure in the production and function of T, B, and natural killer cells. ADA-SCID ex vivo gene therapy can safely restore immune cell function and differentiation, decreasing infection rates similarly to those within a control paediatric population. Despite immunological rescue, ADA-SCID patients develop neurological symptoms which are not improved by, and independent of, ex vivo gene therapy. How mutations in the ADA gene lead to the manifestation of neuropsychiatric phenotypes is unknown and still needs to be investigated. There is currently no human in vitro disease model to study ADA deficiency-induced neuropathology, prohibiting the study of ADA-SCID associated neuropsychiatric symptoms and the development of therapeutic strategies. Furthermore, the possible convergence of molecular pathways dysregulated in ADA-SCID disease with other neurodevelopmental disorders, in particular other rare diseases that involve purine metabolism, might help in identifying potential therapeutic approaches beneficial to the wider neuroscience community. This project will leverage state-of-the-art human stem cell technology to generate a cohort of patient-derived organoids allowing for the dissection of the molecular mechanisms underlying ADA-SCID neuropathology.

Iorio Francesco
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Human Technopole (HT) Computational Biology and Bioinformatics, Drug discovery and design, Omics Sciences (genomics and other omics), Biology of Ageing, Computational Pharmacogenomics 1
Exploiting epigenetic-aging mechanisms for the discovery of cancer therapeutic targets

We will use existing computational tools and develop novel methods to analyse extensive collections of basal methylation profiles from cancer patients, with the primary objectives of i) building improved predictive models of methylation age in cancer patients elucidating the interplay between disease state and ageing, and ii) exploring their impact on methylation patterns, as well as the acquisition of ageing-associated cancer dependencies and potential therapeutic targets. Furthermore, iii) we will characterise more general multi-omics signatures linked to ageing and rejuvenation in cancer patients and use these to iv) computationally map cancer cell lines and their CRISPR-derived genetic vulnerabilities onto ageing-associated processes. Through these analyses, we aim to gain insights into the molecular mechanisms underlying cancer ageing and rejuvenation, along with potential therapeutic implications.

Kalebic Nereo
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Human Technopole (HT) Experimental Pathology, Molecular Oncology, Neurobiology 1
Brain plasticity in glioma

The project focuses on the interactions between glioma cells and their microenvironment. Glioma cells are known to establish various connections with neurons, glia,  blood vessels and other glioma cells. This project aims to dissect the mechanisms through which those bidirectional interactions can promote tumour growth and invasiveness, as well as induce brain remodelling, eventually impacting its function.
The project will be done in a close collaboration with our clinical partners and will involve work on glioma organoids and mouse models as well as genomic and computational approaches.

Kovatcheva Marta
IFOM ETS - The AIRC Institute of Molecular Oncology Biology of Ageing, Drug discovery and design, Molecular and Cellular Biology 1
Novel senolytic targets for the treatment of age-associated diseases

Cellular senescence is a stable form of growth arrest that is resistant to apoptosis and generates an inflammatory secretome. Senescence can be activated by multiple stressors, including DNA damage and oncogene activation. Under normal conditions, senescent cells are eliminated by the immune system. However, under conditions of chronic stress or immunodeficiency, senescence accumulation can lead to persistent inflammation, tissue dysfunction, and chronic disease. Senescent cells accumulate across mammalian tissues with age, and they are causative in many age-associated diseases, including tissue fibrosis, neurodegeneration, and cardiovascular disease. In recent years, the concept of “senolysis,” or pharmacologic targeting for the selective killing of senescent cells, has become an attractive strategy to ameliorate age-associated pathologies; nevertheless, there are few known senolytic agents, and the ones that do exist have limitations relating to efficacy, selectivity, or toxicity.
In this project, we will capitalize on our previous results from a CRISPR/Cas9 screen to identify novel genetic senolytic targets. Using, a combination of molecular and cell biology in vitro and in vivo mouse models, our goal is to understand the fundamental role of these genes in senescence biology and to ultimately develop novel pharmacologic strategies for the therapeutic elimination of senescent cells. 

Legnini Ivano
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Human Technopole (HT) Developmental and Stem Cell Biology, Molecular and Cellular Biology, Omics Sciences (genomics and other omics) 1
Regulation of spatial gene expression territories in neurodevelopment

Across animals, the key to generate complex body plans from a single cell resides in the capacity to generate asymmetries early in development, by establishing spatially distinct gene expression territories. To reproduce and study these events in a reductionist manner, we work with new organoid models of neurodevelopment where precise genetic control (e.g. by synthetic biology and optogenetics) enables to reconstitute in vitro complex signalling events such as morphogen gradients.
By using microscopy, single-cell RNA-seq and spatial transcriptomics data, the candidate will try to understand the principles guiding the emergence of spatial gene expression territories in neurodevelopment, and will then probe their hypotheses for example by genetic perturbations and additional functional genomics approaches.

Mapelli Marina
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European Institute of Oncology (IEO) Developmental and Stem Cell Biology, Molecular and Cellular Biology, Molecular Oncology 1
Molecular principles of intestinal stem cell self-renewal

The PhD project will address the molecular mechanisms of Wnt-dependent self-renewal in the regulation of stem cell activity, tissue homeostasis and oncogenesis, with emphasis on intestinal cancers. Colorectal cancer is a leading cause of death among industrialized nations. A major issue affecting treatment efficacy is the high relapse rate, which largely depends on the presence of deregulated cancer stem-like cells. The normal adult intestinal epithelium is a polarized monolayer constantly being renewed by intestinal stem cells residing at the base of invaginations called crypts, whose proliferation is governed by Wnt3-ligands secreted by Paneth cells acting as niches. Intestinal stem cells undergo planar divisions to regenerate the intestinal epithelium and preserve tissue homeostasis.
The project will address the functional principles of intestinal stem cells self-renewal with a combination of cell biology in artificial niches and organoids, and multi-omics approaches. These studies will shed light on the mechanistics of Wnt-dependent self-renewal, likely paving the way to novel therapeutic strategies to treat intestinal cancers.

Natoli Gioacchino
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European Institute of Oncology (IEO) Epigenetics, Molecular and Cellular Biology, Molecular Oncology 1
Molecular and functional analysis of pancreatic cancer heterogeneity

PDAC is the common solid tumor with the most unfavourable prognosis, with a median life expectancy of a few months. Treatment failures in PDAC are attributed to multiple factors, with one significant determinant being the extensive intra-tumor heterogeneity observable at cellular, architectural and transcriptional levels. Our lab recently developed advanced experimental and computational tools that enabled the molecular characterization of PDAC variants that coexist in every single PDAC. The main focus of this project is an in depth analysis of candidate master regulators of PDAC heterogeneity using a combination of genomics, genome editing and biochemistry.

Pagani Massimiliano
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IFOM ETS - The AIRC Institute of Molecular Oncology Computational Biology and Bioinformatics, Immunology 1
Charting the tumor ecosystem by spatially resolved methodologies

The role of the immune system in tumor progression is nowadays widely accepted. In this context, the regulatory CD4+T lymphocytes are powerful suppressors of the immune-system anti-tumor activity in many solid tumors. Over the last years we have contributed to describe the molecular features of tissue and tumor infiltrating regulatory T cells by both bulk and scRNA sequencing. Intriguingly, emerging evidence suggests that, beyond their immune-suppressive functions, Treg cells are involved in the regulation of the epithelial stem cell niche in different tissues and that specific Treg functions are regulated by the environmental cues and by cell-cell interaction dynamics in the tumor microenvironment. Therefore, drawing a high-resolution map of Treg cell neighborhoods in the tumor microenvironment will give us insights on how Treg cells acquire their specific tumor identity and on their functional state in different tumor niches. 
Toward spatial patterning reconstruction, we are employing the CosMx Nanostring platform that allows to map a thousand transcripts simultaneously at single-cell resolution with high sensitivity. Dedicated computational methods will be then applied to reconstruct from spatially resolved datasets cell-cell interaction networks, responses to environmental cues (e.g.hypoxia) and gene expression patterning of both Treg cells , tumor and stromal cells of the primary tumor and metastatic microenvironment.
We expect that the reconstruction of the tumor microenvironment spatial contexture will shed new light on the existing interplay between tumor and Treg cells and on the niches that sustain the acquisition of the molecular and functional features that make Treg cells more active at tumor sites.

Pece Salvatore
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European Institute of Oncology (IEO) Developmental and Stem Cell Biology, Molecular and Cellular Biology, Molecular Oncology 1
Single-cell resolution and spatial reconstruction of bladder cancer heterogeneity

The project aims to resolve at the cellular level the intra- and extra-tumor heterogeneity of bladder cancer with the specific aim to identify novel prognostic biomarkers of non-muscle-invasive to muscle-invasive disease transition, as well as novel therapeutically actionable vulnerabilities for personalised patients' management. The project will integrate high-dimensional single-cell transcriptomics approaches to resolve the spatial heterogeneity within the primary tumor mass and the microenvironment, in combination with spatial multiplexed immunofluorescence imaging to provide a topological reconstruction of the subblonal heterogeneity suitable to in situ analysis of diagnostic samples from real-life patients.

Pelicci Pier Giuseppe
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European Institute of Oncology (IEO) Computational Biology and Bioinformatics, Epigenetics, Human Genetics and Genomics, Molecular Oncology 1
Non-genetic mechanisms of drug-resistance in Acute Myeloid Leukemia (AML)

AML carries poor prognosis, with a 5-year survival rate below 40%. Standard treatment (“7+3” chemotherapy) did not change in the last 50 years, despite the introduction of targeted drugs. >90% of death is due to the emergence of chemo-resistant relapse. Recent evidence suggests resistance may not be driven by traditional genetic mutations, but rather by the ability of leukemic cells to dynamically adapt their phenotypes (phenotypic plasticity). Our project delves into the mechanisms of this non-genetic chemoresistance in AML.
We've made significant strides in understanding non-genetic chemoresistance in AML (manuscript in preparation). We developed the first AML Patient-Derived Xenograft (PDX) models of chemioresistance. Utilizing a powerful combination of cutting-edge multi-omic technoclogies – including whole-exome sequencing, transcriptional lineage tracing, and single-cell RNA sequencing – we comprehensively characterized the genetic and phenotypic features of chemoresistant leukemic blasts. Our findings revealed that chemoresistance doesn't involve specific DNA mutations or favor particular cellular clones. However, chemoresistant leukemia cells exhibit unique transcriptional signatures, including the activation of specific intracellular signaling pathways. Remarkably, this chemio-resistant gene signature possess a potent prognostication power in large cohorts of AML patients, and targeting its top marker gene completely reversed chemoresistance in our PDX models.
This ongoing project has several key aims: Unravel the molecular mechanisms behind the observed reversal of chemoresistance; ii) Validate the effectiveness of targeting other members of the chemoresistance signature in vivo; iii) Translate these findings to patient care through collaboration with the Hematology Division at IEO; iv) Design novel therapeutic strategies to overcome chemoresistance based on the identified mechanisms.
The PhD student will receive comprehensive training, becoming familiar with both core wet-lab techniques (mouse genetics, molecular and cellular biology, transcriptional lineage tracing, multi-omic single-cell approaches, high-resolution imaging) alongside computational biology approaches (single-cell analysis, cancer genomics, clinical data modeling, multi-omic data integration), and will then be assigned specific tasks within the project, contributing to these vital areas of research.

Pelicci Pier Giuseppe
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European Institute of Oncology (IEO) Computational Biology and Bioinformatics, Epigenetics, Human Genetics and Genomics, Molecular Oncology 1
Breast-cancer cell-phenotypes selected during metastatization and treatment

Genetic and phenotypic heterogeneity underpin tumor evolution and are a constant trait of the transformed phenotype, critical for metastatization and drug resistance. We have recently established robust protocols to investigate simultaneously genetic and transcriptional clonal evolution by DNA and RNA barcoding at single-cell level (https://doi.org/10.1158/0008-5472.CAN-22-2717). We are applying this platform to the analysis of breast cancer dissemination, specifically focusing on the longitudinal evolution of aggressive clones from the primary tumor, to the circulating tumor cells, micrometastasis and to lung/liver metastases under therapeutic pressure (chemotherapy ± immunotherapy), using PDXs and syngeneic mouse models. Barcoded tumors, CTCs, micrometastasis and metastases are analyzed through a multi-omic approach that includes clonal reconstruction through the RNA/DNA barcodes, mutational profiling through WES and transcriptional characterization by single-cell RNA sequencing. We identified unique clonal and transcriptional patterns following therapeutic pressure, which sustain the chemoresistant and metastatic phenotype and the novel therapeutic targets are being validated through in-silico simulations and computational tools as well as by in vivo experiments, using murine and zebrafish models.
The PhD student will receive comprehensive training, becoming familiar with core wet-lab techniques (mouse genetics, molecular and cellular biology, transcriptional lineage tracing, multi-omic single-cell approaches, high-resolution imaging) alongside basic computational approaches (single-cell analysis, cancer genomics, clinical data modeling, multi-omic data integration), and will then be assigned specific tasks within the project, contributing to these vital areas of research.

Pelicci Pier Giuseppe
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European Institute of Oncology (IEO) Computational Biology and Bioinformatics 1
Functional and genetic characterization of Enhancer-promoter networks in breast cancer

While over 90% of cancer deaths are attributed to metastasis, we currently lack effective therapies that target this specific process. Emerging research suggests that metastasis is driven by a combination of genetic (SNVs and chromosomal instability) and non-genetic factors (transcriptional and metabolic reprogramming). Non-genetic factors can be triggered by adaptations to the surrounding environment (like the switch from epithelial to mesenchymal cells ; EMT). However, the exact link between these factors and how they contribute to metastasis remains largely unknown.
Our research group has made significant strides in understanding the role of DNA damage in cancer. Previous work identified that DNA accumulates in the regulatory regions (promoters) of active genes in healthy breast cells. Strikingly, these same fragile promoters become more likely to be rearranged in the genomes of breast cancer patients [Nature Genetics, 2019]. Building on this discovery, we recently identified approximately 2,000 fragile enhancer elements that all interact with a protein called GRHL2, a pioneer transcription factor involved in the maintenance of the epithelial phenotype, and  are frequently mutated or rearranged in breast cancer patients (unpublished data). This project aims to investigate whether these genetic alterations in GRHL2 enhancers disrupt communication with their target genes within the 3D structure of the genome. We hypothesize that such disruptions weaken epithelial gene programs and promote the development of mesenchymal features in rare cells that intiate the metastatic cascade.
The project will utilize a powerful arsenal of cutting-edge chromatin technologies readily available in our lab, including: mapping DNA damage (DSB and SSB) with single-nucleotide precision (BLISS and GLOEseq); chromatin mapping of key TF, histone marks and DNA repair proteins (ChIP-seq); iii) visualizing how DNA is folded in the nucleus (Hi-C and Hi-ChIP); measuring gene activity (RNAseq) in control and genetically engineered (by double-stranded RNA-mediated interference, inducible RNA silencing, CRISPR/Cas9 Genome editing, etc.). We will first reconstruct the communication network between GRHL2 enhancers and their target promoters and then functionallycharacterize the specific mutations and rearrangements affecting GRHL2 enhancers in breast cancer patients. Using genome editing in normal and cancer cells, we will then define the functional role of these alterations in promoting metastasis. Finally, we will analyze large patient datasets to assess the clinical significance of GRHL2 enhancer alterations and their target genes. This project holds great potential to revolutionize cancer research, by unveiling fundamental mechanisms of gene regulation and cancer evolution, which may lead to personalized medicine with novel biomarkers and therapeutic targets.
The candidate PhD student will work on the analysis of various types of genomic data generated from the project. Specifically, his/her role will involve: i) DNA Damage Mapping Analysis: Utilizing BLISS and GLOEseq data, student will quantify and map DNA damage sites with high resolution, differentiating between single-strand and double-strand breaks. This will lead to the identification of vulnerable regions and their implications in cancer development. Ii) Chromatin Accessibility and Protein-DNA Interaction Profiling: Through ChIP-seq data analysis, students will chart the landscape of transcription factor binding sites, histone modifications, and DNA repair protein occupancy. Integrative analysis with RNAseq data will help elucidate the dynamics of chromatin changes and gene expression regulation during cancer evolution. Iii) 3D Genome Organization: Analyzing Hi-C and Hi-ChIP data, students will reconstruct the 3D architecture of the genome, revealing how DNA folding influences gene regulation. By correlating genome folding with genetic and epigenetic changes upon GRLH2 KD, the project aims to uncover structural alterations contributing to misregulation in cancer. iv) Gene Expression Profiling: RNAseq data will be analyzed to measure gene activity changes resulting from perturbation of GRLH2. v) Functional Genomics: Analyzing data from genome-edited cell lines, students will determine the effects of specific mutations and alterations in GRHL2 enhancers on cancer metastasis. This will involve assessing changes in gene expression, chromatin state, and cell behavior in response to genome editing. vi) Clinical Data Integration: Large patient datasets will be analyzed to assess the clinical significance of identified GRHL2 enhancer alterations. This will include statistical analyses to correlate genomic alterations with patient outcomes, identifying potential biomarkers for breast cancer prognosis and treatment response. Vii) Cross-Dataset Integration: A critical component will be the integration of all collected datasets (DNA damage, ChIP-seq, RNAseq, Hi-C/Hi-ChIP, and clinical data) using advanced computational methods. This integrative approach will allow for a comprehensive understanding of the molecular mechanisms driving breast cancer metastasis. Throughout their research, PhD candidates will be encouraged to develop novel computational methods for data integration, enhancing their skills in bioinformatics and systems biology. Collaboration with bioinformaticians and computational biologists will be crucial in achieving robust analyses and innovative insights into cancer genomics.

Pesole Graziano
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University of Bari Computational Biology and Bioinformatics, Epigenetics, Molecular and Cellular Biology 1
Bioinformatics approaches for the analysis of the genome and epigenome from single molecule sequencing data

The recent tremendous advancements in genomic technologies have revolutionized the field of genotyping and clinical genomics, providing unprecedented insights into the genetic basis of human health and disease. In particular, the advent of single molecule sequencing platforms, with their ability to generate long read sequencing data, has significantly expanded the repertoire of tools available for comprehensive genetic analysis. 
This PhD project is aimed at developing innovative bioinformatics approaches for fully exploiting single molecule sequencing data in order to reliably reconstruct the maternal and paternal genomes and methylomes and detect large structural variants and other complex genomic rearrangements escaping short-read sequencing analysis. The development of computational workflows for the investigation of family pedigrees will also be addressed, as this may represent a powerful approach for the identification of transmitted alleles and/or de novo mutations that may confer susceptibility to the disease. 
The above bioinformatics approaches will be applied also to re-evaluate patients with “orphan diagnosis”, for which WGS analysis based on short reads was uninformative for the diagnostic assessment.   

Pinheiro Fernanda
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Human Technopole (HT) Computational Biology and Bioinformatics, Microbiology and Microbiome, Evolutionary Biology 1
Predicting antibiotic resistance evolution

Ecological and evolutionary processes of microbial pathogens are key to understanding antibiotic resistance and human health. Antibiotic treatment is a complex interplay of antibiotic chemistry, bacterial physiology, and ecology. Increasing evidence indicates that antibiotic resistance evolution cannot be decoupled from bacterial physiology and environmental conditions. In real-life situations, bacteria are rarely in isolation and often grow in the presence of other microbes and/or environmental conditions that are not constant. How can we predict antibiotic resistance evolution in such cases? 

In this project, we will interrogate the evolution of antibiotic resistance in complex scenarios, including changing environments and interactions between members in simple microbial communities. We will combine theory and experiments to develop computable models of drug action grounded on cell metabolism models and mechanistic models of evolutionary response for antibiotics targeting different cellular processes (e.g., translation, transcription, cell-wall inhibitors). By informing rational protocols for sustainable antibiotic use, methods developed in this program will help the fight against the growing and alarming problem of antibiotic resistance.

Polo Simona
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IFOM ETS - The AIRC Institute of Molecular Oncology Computational Biology and Bioinformatics, Molecular Oncology 1
Elucidating the impact of alternative splicing in colorectal cancer via multi-omics data integration

Tumor-specific alternative splicing (AS) events play a pivotal role in the adaptive mechanisms of cancer cells during tumorigenesis. Recent findings from our laboratory indicate that beta-catenin exerts a significant influence on AS reprogramming throughout the onset and progression of colorectal cancer (CRC).
This project aims to elucidate the molecular mechanisms underlying beta-catenin's impact by employing a combination of genetic engineering and integrative multi-omics approaches. The student will conduct comprehensive analyses and integration of RNA-seq, RIP-seq, proteomics, and imaging data derived from diverse model systems. Through these efforts, we seek to unveil and characterize the key molecular players driving alternative splicing reprogramming during CRC evolution with the final goal to identify new molecular vulnerabilities and treatment strategies.

Polo Simona
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IFOM ETS - The AIRC Institute of Molecular Oncology Drug discovery and design, Molecular and Cellular Biology, Molecular Oncology 1
Unraveling the role of oncogenic deubiquitinating enzymes in colorectal cancer

In over 85% of cases, somatic gene mutations in APC or β-catenin deactivate the destruction complex, resulting in β-catenin stabilisation in the nucleus, a critical step in colorectal cancer (CRC) tumorigenesis. While cytoplasmic complexes regulating β-catenin have been extensively studied, mechanisms governing its stability or degradation in the nucleus, under physiological Wnt-on conditions or in CRC aberrant activation, remain elusive.
This project aims to bridge this gap by identifying oncogenic deubiquitinating enzymes (DUBs) responsible for removing the ubiquitin-destruction signal from nuclear active β-catenin. State-of-the-art CRISPR-based genetics combined with cell biology and imaging techniques will be used to identify DUBs whose depletion destabilises β-catenin. Targets identified will then be validated by orthogonal approaches. Using in vitro deubiquitination assays, the candidate will characterize whether β-catenin is a direct substrate of the identified DUBs. To understand whether the validated DUBs may represent therapeutic targets, expression analysis in CRC will be performed in silico, as well as further validation by qRT-PCR, IHC, and RNAscope on CRC primary tumors and PDOs. If successfully completed, this project holds significant implications, as cancer-associated DUBs represent potential drug targets and are being fast-tracked as new pharmaceutical targets.

Pravettoni Gabriella
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European Institute of Oncology (IEO) Medical Humanities 1
eHealth technologies to promote primary cancer prevention

We are inviting applications from highly motivated candidates interested in pursuing a PhD within a European doctoral program. This proposed research project focused on the study of decision-making processes in cancer screening for supporting early diagnosis, and the adoption of risk-reduction behaviors. This proposed project aims to develop evidence-based interventions and technologies to increase participation in screening programs, provide a psycho-social risk profile, promote early diagnosis, and encourage healthy behaviors.
PhD candidate will have the opportunity to conduct cutting-edge research in the field of cognitive psychology, health and clinical psychology and oncology. Under the guidance of experienced advisors, PhD candidate will design and execute studies aimed to explore inner and external determinants of decisions in the domain of cancer screening and prevention behaviors, and on the role the eHealth Ecosystem as aid to promote cancer prevention. The PhD candidate will be part of the Applied Research Division for Cognitive and Psychological Science of IEO. The Division is affiliated to the Department of Oncology and Hemato-Oncology of the University of Milan (UNIMI) that has extensive research collaboration, both internally and with other research environments nationally and internationally.
The successful PhD candidate will be involved in various activities, including conducting research in the field of General and Health Psychology, contributing to the development and optimization of protocols, analyzing and interpreting data and present findings at the group meeting and conferences, writing and publishing scientific articles in international journals.

Pravettoni Gabriella
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European Institute of Oncology (IEO) Medical Humanities 1
Digital solutions to tackle mental health in cancer patients and their families

We are inviting applications from highly motivated candidates interested in pursuing a PhD within a European doctoral program. This proposed research project focused on the use of health ecosystems for the medical education training, and psychological and neuropsychological screening of patients with cancer. A growing body of evidence highlighted the key role of the medical education training in shaping the knowledge, skills, and attitudes of healthcare professionals, ensuring they are equipped to provide high-quality care to patients. Moreover, recent evidence suggested the importance to be able provide a tailored psychological assessment in order to early identify patients at risk of distress.
Within this framework, PhD candidate will design and execute studies aimed to develop educational technologies for healthcare professionals for supporting the acquisition of hard and soft skills in the psychological and clinical assessment, and interventions to menage psychological distress, and neuro-psychological burden in patients with cancer. Further, PhD candidate will contribute to collect additional knowledge and expertise about the psychological screening aids and interventions for patients with cancer.
The PhD candidate will be part of the Applied Research Division for Cognitive and Psychological Science of IEO. The Division is affiliated to the Department of Oncology and Hemato-Oncology of the University of Milan (UNIMI) that has extensive research collaboration, both internally and with other research environments nationally and internationally.
The successful PhD candidate will be involved in various activities, including conducting research in the field of General and Health Psychology, contribute to the development and optimization of protocols, analyzing and interpreting data and present findings at the group meeting and conferences, writing and publishing scientific articles in international journals.

Rescigno Maria
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Humanitas University Immunology 1
Analysis of the role of the choroid plexus and the microbiota in brain tumor metastasis formation

The laboratory identified two novel vascular barriers: one in the intestine (GVB) and another in the choroid plexus (PVB). These barriers have been characterized in various pathological scenarios, revealing a tightly regulated permeability during inflammatory processes. They play a crucial role in controlling what substances can enter or exit the bloodstream, thus influencing the communication between the gut, liver, and brain.

Specifically, we have demonstrated that the choroid plexus serves as the primary gateway for large molecules and immune cells to access the brain. Our preliminary data indicate that the PVB is modulated even before tumor metastasis formation, suggesting that the presence of a primary tumor may shape the PVB to prepare the soil for tumor cell seeding in the brain. We hypothesize that the PVB is involved both in brain tumor metastasis formation and in the infiltration of immune cells. We will employ conditional environmental and genetic mouse models to modulate the PVB so to evaluate its role in metastasis formation. Metabolomics, microbiota and immune cell profiling will be used to evaluate their possible involvement in PVB opening/closure. Targeting the PVB may lead to new prevention and therapeutic approaches for the management of brain metastases.

Santaguida Stefano
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European Institute of Oncology (IEO) Molecular Oncology 1
Deciphering and exploiting aneuploidy in cancer

Genome integrity is maintained through faithful chromosome segregation at each cell division, in which one copy of a duplicated chromosome is deposited in each daughter cell. Errors in this process lead to aneuploidy, a condition in which cells carry an abnormal karyotype. Aneuploidy is the most common chromosome aberration in humans and is a widespread feature of solid tumors. Our work seeks to decipher how aneuploidy affects cell physiology by identifying and characterizing the pathways deregulated in human cells following chromosome segregation errors. To tackle this biological question, we use a combination of cell biology, molecular biology and genome editing techniques. Our goal is to expand our understanding of the biology of aneuploid cells and to identify specific features that can be targeted in cancer therapy.

Scaffidi Paola
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European Institute of Oncology (IEO) Epigenetics, Molecular and Cellular Biology, Molecular Oncology 1
CRISPR-based Saturation Gene Editing to dissect epigenetic mechanisms promoting cancer development

Our laboratory investigates how epigenetic mechanisms regulate basic cell function and how their dysregulation favors cancer development, with a particular focus on chromatin-based mechanisms. By combining experimental and computational approaches, we seek to understand: (i) the epigenetic basis of malignant cell phenotypes at various disease stages; (ii) associated vulnerabilities that can be exploited to interfere with the disease. 
In this project, we aim to understand how mutations in chromatin modifiers, which are widely selected across all cancer types, impact the cellular response to oncogenes. Using the histone acetyl-transferase p300 as a paradigm, we will employ CRISPR-based Saturation Genome Editing (Findlay et al. Nature 2018) to model thousands of single-nucleotide substitutions detected across cancer types. Many of these variants appear to be under positive selection in patients, but their functional impact has been unclear. We will generate libraries of cells engineered to express individual variants from the endogenous locus, and use parallel functional assays that select mutations affecting - in various combinations - gene expression, histone marks, genome integrity and cellular fitness in normal or oncogene-challenged cells. Characterization of selected mutants will finally employ a combination of genomics (e.g. bulk and single-cell RNA-seq, ATAC-seq, ChIP-seq), quantitative microscopy and in vivo assays.

Scaffidi Paola
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European Institute of Oncology (IEO) Epigenetics, Computational Biology and Bioinformatics, Molecular Oncology, Omics Sciences (genomics and other omics) 1
Understanding and predicting the response to epigenetic drugs: from a robust regulatory network to acquired vulnerabilities

Our laboratory investigates how epigenetic mechanisms regulate basic cell function and how their dysregulation favors cancer development, with a particular focus on chromatin-based mechanisms. By combining experimental and computational approaches, we seek to understand: (i) the epigenetic basis of malignant cell phenotypes at various disease stages; (ii) associated vulnerabilities that can be exploited to interfere with the disease. 
Targeting of diverse classes of epigenetic regulators has shown efficacy in various cancer types and limited toxicity in normal tissues. However, the response of cancer cells to epigenetic drugs is highly variable, showing poor correlation with genetic background. In this project, we will use various computational strategies to examine how cumulative disruption of epigenetic regulation in cancer cells creates synthetic lethal vulnerabilities. By combining analysis of publicly available and ad-hoc generated datasets (bulk and single-cell RNAseq, Exome-seq, and drug sensitivity data) with artificial intelligence approaches (machine learning and artificial neural networks) we will identify features that predict sensitivity to epigenetic drugs. A particular focus will be on combined alterations in distinct classes of epigenetic regulators (e.g. chromatin remodellers, histone modifiers, histone variants, etc.) that destabilize the epigenetic regulatory network. A solid expertise in programming and previous experience with relevant approaches is required.

Schaefer Martin
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European Institute of Oncology (IEO) Computational Biology and Bioinformatics, Epigenetics, Omics Sciences (genomics and other omics) 1
The hidden drivers of cancer

Cancer is driven by alterations on all molecular levels. While our knowledge about the contribution of point mutations to the phenotypic hallmarks of cancer has advanced substantially over the last decade, we still need to solve the puzzle of how the numerous epigenetic changes and amplifications and deletions of large genomic regions are related to cancer initiation and progression. We are looking for a computational PhD student to develop models of selection to identify novel drivers of carcinogenesis.
The project will combine methods from the fields of population genetics, machine learning and network biology to create a systems biology understanding of how molecular changes act together to transform healthy into cancer cells. The successful candidate will work together with other members of the lab as well as with wet lab and clinical collaborators.
This project is related to our previous work, in particular:
Heery and Schaefer. NAR. 2021 (doi.org/10.1093/nar/gkab1167)
Alfieri, Caravagna and Schaefer. Nat Comm. 2023 (doi.org/10.1038/s41467-023-39313-8).

Scita Giorgio
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IFOM ETS - The AIRC Institute of Molecular Oncology Computational Biology and Bioinformatics, Experimental Pathology 1
Identification of a mechano-based prognostic score in breast cancer

In this study, we aim to identify histomorphological signatures in breast cancer, using mechanics to predict disease outcomes through AI. We focus on cell intrinsic and extrinsic mechanical attributes: In the first case, we will determine nuclear morphometrics and chromatin condensation patterns, distinguishing between normal and cancerous cells, to reflect the mechanical stress history of tissues[1-6]. Combining these parameters with the analysis of specific biological markers (e.g., YAP1&TAZ, cGAS/STING pathway, immune infiltrates), we expect to enhance our predictive model. We will further leverage the structural alterations of the extracellular matrix that invariably accompany BC lesions, focusing on label-free two-photon based analysis of desmoplastic fibrillar stroma. Next, we will use Random Forest machine learning to integrate mechano-attributes, multiplexed antibody profiling, and spatial omics analysis of the tumor immune ecosystem. This will create a detailed, AI-based Tumor Mechan-Omics Score with comprehensive multiparametric inputs.
Our preliminary tests on triple-negative and ductal carcinoma in situ, along with invasive ductal carcinoma using our established Mechanomec platform, show promise for stratifying cases based on clinical histories. Future applications will extend to metastatic lesions, identifying those more responsive to immune-checkpoint and mechano-drug treatments.
References:
1.    Frittoli, E. et al. Nat Mater 22, 644-655 (2023)
2.    Villa, S. et al. Eur Phys J E Soft Matter 45, 50 (2022)
3.    Nader, G.P.F. et al. Cell 184, 5230-5246 e5222 (2021)
4.    Palamidessi, A. et al. Nat Mater 18, 1252-1263 (2019)
5.    Atia, L. et al. Nat Phys 14, 613-620 (2018)
6.    Grosser, S. et al. Physical Review X 11, 011033 (2021)

Segata Nicola
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University of Trento Computational Biology and Bioinformatics, Microbiology and Microbiome 1
Microbiome signatures of early on-set colorectal cancer risk factors

The research program is part of the project "PROSPECT" funded by Cancer Research UK, the National Cancer Institute, the Bowelbabe Fund for Cancer Research UK and Institut National Du Cancer through Cancer Grand Challenges. The overall aim of PROSPECT is to identify and understand the processes through which different biological and environmental factors cause early-onset cancers (EOCRC), and specifically the work packages led by prof. Nicola Segata are focusing on the role of the microbiome in such processes.
The researcher will develop computational methods to be used to address these questions: 1) Identify gut metagenomic biomarkers for active EOCRC; 2) Identify prospective microbiome biomarkers of EOCRC; 3) Assess the transmissibility of EOCRC biomarkers and risk factors. This will be performed by developing new computational analyses, statistical meta-analyses, and machine-learning investigations applied on newly collected samples from the project and samples from other projects and the public domain.

Segata Nicola
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European Institute of Oncology (IEO) Metagenomics, Microbiome, Bacterial Infection, Computational Biology and Bioinformatics 1
Metagenomic and metabolomic characterization of Lyophilized Fecal Microbiome Transfer for Primary Clostridioides difficile Infection

Primary Clostridioides difficile infection (pCDI) is a gastrointestinal infection that presents with diarrhea , fever and abdominal pain and is often resistant to antibiotic therapy. pCDI is often a consequence of previous exposure to antibiotics that disrupt the balance of healthy microbes that reside in our gut. Fecal microbiota transplantation (FMT), the introduction of a healthy microbial community from a healthy donor, has been shown to be safe and highly effective in patients who experience recurrence of CDI, but was not vigorously tested in primary infection. FMT can also fight other deleterious microbes that might reside in the gut. Since FMT contains live bacteria, it needs to be kept frozen until administration. In the context of consortium “Donate project” (JPIAMR-ACTION call) our partners have developed a dry compound that does not need freezing (Lyo-FMT) and aim to assess its efficacy for pCDI. We will investigate and study the success of Lyo-FMT using a computational multi-omics approach (metagenomics and metabolomics) in order to investigate the microbiome engraftment and his activity against CDI. The easy-to-administer product will restore, without affecting microbial viability, the healthy bacterial community, fight infection and reduce the use of antibiotics. If effective, this study will revolutionise the treatment of this worldwide distributed infection.

Sigismund Sara
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European Institute of Oncology (IEO) Molecular and Cellular Biology, Molecular Oncology 1
Role of endocytosis in cell plasticity, breast cancer progression and metastasis

Our laboratory is interested in understanding the role of endocytosis in epithelial-to-mesenchymal transition (EMT), cancer cell invasion and metastasis.  Through the study of the endocytic protein Epsin 3, whose overexpression in breast cancer correlates with poor prognosis and metastasis, we have recently discovered that breast epithelial cells are capable of acquiring a plastic, hybrid EMT phenotype, through the establishment of an endocytic-based circuitry, which renders them prone to perform in situ-to-invasive transition, typical of invasive breast carcinomas. 
The overall goal of this project is to characterize the relevance of EPN3-induced partial EMT in breast cancer.  Specifically, we aim to investigate:
i) the molecular mechanism of EPN3-induced ECAD endocytosis; 
ii) the plasticity of EPN3-induced pEMT vs. full EMT in inducing invasive phenotypes;
iii) inhibitors of EPN3-induced invasive phenotypes in an ex vivo system (e.g. breast cancer organoids).

Soranzo Nicole
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Human Technopole (HT) Single Cell, Genetics, Immunology 1
Statistical genomics of population-scale single-cell data

The development of ever more sophisticated, massively parallel tools to scan the sequence and function of the human genomes has fostered a revolution in our understanding of how inherited genetic variation contributes to human traits and diseases.
Over the course of the last 15 years, our group has been at the forefront of studies investigating the genetic control of different layers of biological information, captured through so called multi-omic techniques (eg proteomics, metabolomics, transcriptomics etc). Through integrative analyses anchored on genetic information, we have been able to map the function of many loci predisposing to complex human diseases, and to formulate new therapeutic hypotheses based on genetic data.
The student will have access to cutting-edge, multidimensional datasets, including a single-cell transcriptomics dataset in thousands of individuals with linked multiomic and health data information. The main goal of this PhD project will be to deploy advanced analytical approaches based on machine learning and statistical analysis to model the effect of genetic variation on complex biological data and to predict the onset of debilitating human diseases.

Testa Giuseppe
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Human Technopole (HT) Developmental and Stem Cell Biology, Neurobiology, Omics Sciences (genomics and other omics) 1
Dissecting gene-environment interactions in human brain development and neurodevelopmental disorders through brain organoid and single cell multi-omic modelling

The human brain forms through a complex and coordinated series of developmental processes that originate an impressive variety of cell populations organized in interconnected networks across multiple scales. The introduction of cell reprogramming and 3D brain organoid technologies has been transforming the study of human neurobiology by overcoming the inherent inaccessibility of the spatial and temporal dynamics of in vivo human neurodevelopment and recapitulating its salient features in vitro. 
Integrating brain organoid with single-cell multiomics modelling this PhD post is inserted within our long-standing investigation of the molecular mechanisms underlying human neurodiversity, focusing on how genetic and environmental factors interact in the context of sensitive windows of neurodevelopment.
The project will leverage comprehensive atlases of the human brain and brain organoids at single cell resolution, relying on both publicly available and in-house produced single cell multi omics data (transcriptomics, spatial transcriptomics and epigenomics), using advanced computational approaches for data integration and analysis.
The atlas will be employed as an interpretative layer to project and decode brain organoids multi-omic data from cohorts of neurodiverse individuals. 
Experimental activities including cell reprogramming, (epi)genome engineering, brain organoid modelling and a host of functional assays will be carried out to dissect the impact of specific environmental factors on multiple genetic backgrounds. 
The molecular data generated will be systematically integrated with deeply phenotyped cohorts to identify risk and protective factors for mental health.

Tripodo Claudio
IFOM ETS - The AIRC Institute of Molecular Oncology Computational Biology and Bioinformatics, Immunology, Pathology 1
Exploring the tumor ecosystem in the emerging scenario of cancer in beta-thalassemia

Key elements of the pathological homeostasis of beta-thalassemia patients, such as systemic tissue hypoxia and iron overload, are likely to influence the formation of the hematopoietic and immune interfaces that characterize cancer as a complex and dynamic ecosystem. Our preliminary findings suggest that there may be phenotypical and molecular traits linking the deregulated myelopoiesis observed in a well-established beta-thalassemia transgenic mouse model (Hbbth3/+) with the hematopoiesis seen in cancer-bearing hosts. The objective of this project is to employ a beta-thalassemia disease model to explore the influence of aberrant hematopoietic niches, persistent systemic hypoxia, and disrupted iron metabolism on the modulation of innate and adaptive immune responses that are associated with cancer.

Vannini Alessandro
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Human Technopole (HT) Structural biology 1
Extra transcriptional roles of human RNA Polymerase III

RNA polymerase (Pol) III transcribes essential RNAs, including tRNAs, the 5S rRNA and the U6 snRNA, with the help of transcription factors TFIIIB and TFIIIC. Recent findings point to a broader role of the Pol III apparatus in several processes, such as cytoplasmic viral detection, retrotransposon's integration, nucleosome positioning, global and sub-nuclear organization and control of pervasive Pol II transcription. These "extra-transcriptional" functions depends on coordinated interactions between the Pol III apparatus and other macromolecular machineries, including SMC complexes and chromatin remodellers.
The aim of this proposal is to uncover the molecular mechanisms underlying the transcritpional mechanisms and extra-transcriptional functions of the Pol III transcription apparatus, using an integrated structural biology approach focused on state-of-the-art cryo-elctron microscopy.

Various PIs at TIGEM
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Telethon Institute for Genetics and Medicine (TIGEM) Human Genetics and Genomics, Computational Biology and Bioinformatics 3
Projects will be identified among the ones available at TIGEM

The actual research projects will be identified among the research lines offered at TIGEM. Check the webpage for details:

www.semm.it/TIGEM_positions

 

Various PIs at CEINGE
Center for Genetic Engineering (CEINGE) Human Genetics and Genomics, Molecular Oncology 1
Projects will be identified among the ones available at CEINGE

The actual research projects will be identified among the research lines offered at CEINGE. Check the website for details:

https://www.ceinge.unina.it/en/faculty-list

Zerial Marino
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Human Technopole (HT) Molecular and Cellular Biology, Advanced Light Microscopy, Biophysics 1
Membrane dynamics and tissue morphogenesis

The Zerial Group has a long-standing interest in endocytosis - from its molecular mechanisms to the role of the endocytic machinery in cell and tissue function. The Group chose the mammalian liver as a model system as it is a crucial regulator of many physiological processes. Cellular trafficking and endocytosis are directly responsible for the proper localisation of polarity regulators in hepatocytes. The PhD candidate will investigate how molecules self-assemble to create an endosome, how endosomes control cell organisation, and how cells self-organise to determine the structure of the liver.
For more information about the Zerial Group and its research programmes visit https://zeriallab.org/

Zerial Marino
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Human Technopole (HT) Protein Biochemistry, Endocytosis and trafficking, Biophysics 1
Biochemical and biophysical approaches to study receptor endocytosis and endosomal membrane fusion

The Zerial Group works on endocytosis - from its molecular mechanisms to implications in cell and tissue organisation. Its interests range from the assembly and functional characterisation of the endosomal fusion machinery to establishing hepatocyte cell polarity and liver tissue structure and function. The Group adopts a unique interdisciplinary approach that combines biochemical and biophysical methods with advanced light microscopy, cell biology and computer-aided three-dimensional tissue reconstruction. The PhD candidate will investigate protein compartmentalisation on endosomal membranes using in vitro and in vivo techniques and how it controls receptor endocytosis and endosomal membrane fusion.
For more information about the Zerial Group and its research programmes visit https://zeriallab.org/ 

Zerial Marino
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Human Technopole (HT) Computational Biology and Bioinformatics, Mathematical and computational modelling 1
3D reconstruction and image analysis of liver tissue

The Zerial Group has a long-standing interest in endocytosis - from its molecular mechanisms to the role of the endocytic machinery in cell and tissue function. The Group chose the mammalian liver as a model system as it is a crucial regulator of many physiological processes. The PhD candidate will develop image-based computational approaches to recreate the complex tissue architecture of the healthy and diseased liver from microscopy data and extract quantitative parameters. The candidate will generate three-dimensional computational models of human liver tissue at different disease stages and identify structural cellular and tissue parameters correlating with disease progression.
For more information about the Zerial Group and its research programmes visit https://zeriallab.org/