Transcriptional and Epigenetic mechanisms provided by Noncoding RNAs in human cancer.
Background: The spatial and temporal heterogeneity characterizing cancer presents a major hurdle to both basic and translation research. Within the same tumor, cancer cells can behave differently with some of them acquiring the ability to adapt in response to harsh or even hostile conditions, produced either by the host or following cancer treatment. In recent years, it has become increasingly evident that non-coding mechanisms play an important role in gene regulation. Short (microRNAs) and long non-coding RNAs (lncRNAs) as well as non-coding DNA elements (enhancer, silencer), have emerged as key elements in the adaptive response mechanisms and in the transcriptional/epigenetic reprogramming of cancer cells, which occur during cancer evolution and in the most aggressive cases of the disease, such as metastatic spread or tolerance/resistance to therapy. These RNA elements are also extremely attractive for applied medicine, as they could be exploited to provide a new generation of targets for therapeutic/theranostic applications with unprecedented sensitivity and specificity.
Aim: This project is aimed at investigating the role noncoding RNAs and DNA elements play in the adaptive response of breast cancer cells following anticancer therapies and in the context of advanced 3D models and primary tumor organoids. The candidate will use cutting-edge genomic approaches to achieve a high-resolution characterization of the transcriptional/epigenetic landscape of cancer cells, focusing on their evolutionary trajectories that will be characterized in time and space. The ultimate goal will be to gain insight into the genetic and epigenetic factors that hinder the success of established anticancer therapies.
Methodology: The project is highly interdisciplinary. We will use as model system stroma-enhancer cancer organoids, a sort of "cancer avatars", which mimic the 3D spatial tissue organization and maintain the genetic and phenotypic heterogeneity of their tissue of origin. The candidate will exploit cutting-edge approaches, including state-of-the-art genomic platforms (i.e. RNAseq, ATACseq, DNAseq, Genomic Barcoding, Single-Cell sequencing), genetic interrogation by multiplexed CRISPR/cas9 system (CRISPRi/a, CROP-seq, Perturb-seq approaches) and novel emerging methodologies that will be developed as part of the project (e.g. Spatially-resolved omics).
Please note: the position related to this project can be assigned either to the molecular oncology or computational biology curriculum, depending on the background of the successful candidate.