How tumor and bacteria cells survive stress: drug-induced mutagenesis in cancer evolution and therapeutic resistance
During tumorigenesis, cancer cells forgo the cellular cooperation and the regulatory mechanisms that preserve homeostasis in multicellular organisms, leading to a breakdown in cellular control. Notably, cancer cells resemble features of unicellular organisms in many of their hallmarks:
- In a bacterial population, each microorganism strives and competes with the others for individual survival.
- Cellular growth is regulated by the need of accessible nutrients: as long as nutrients are available, bacteria grow and proliferate with unlimited potential and without undergoing senescence. Tumor cells display replicative immortality, achieved through reactivation of telomerases and bypassing oncogene-induced senescence.
- Cancer cells and bacteria proliferation are insensitive to inhibitory signals coming from the environment, such as contact inhibition or disruption of tissue boundaries.
- Cancer metabolism is mainly sustained by anaerobic glycolysis (the so-called Warburg effect), which is the prevalent energy source among bacteria.
- At the population level, competition among individuals instead of collaboration occurs. In fact, cancer develops through an ongoing selection and expansion of progressively fitter clones, a pattern closely related to the asexual reproduction observed in bacteria. This mechanism of Darwinian selection is favored by an increased frequency of mutations (i.e. the mutation rate), that promotes generation of fitter individuals.
- Relatedly, cancers often display forms of genetic instability that foster the accumulation of mutations and, similarly, hypermutating individuals in a bacterial population are often positively selected.
- During the metastatic cascade, cancer displays clonogenic and colony-forming ability similarly to bacteria. Indeed, metastatic cells avoid anoikis and survive as single migrating cells that are later able to expand to form fully-blown lesions.
Recently we found that colon cancers that were treated with EGFR or BRAF inhibitors down-regulated the expression of high-fidelity DNA repair proteins and increased that of error-prone DNA repair proteins, affecting the mutational potential (Russo et al Science 2019). These results suggest that tumor cells, like unicellular organisms, adapt to therapeutic pressures by enhancing their mutability.
Based on the above, the project will dissect the mechanistic processes and the therapeutic implications of considering tumors growth as an atavistic form of life, subverting multicellularity laws and behaving as single competing units in a community much like bacteria.
The successful candidates will exploit functional genomics and computational approaches to study how targeted therapies and immunomodulation affect DNA repair processes in patient derived colorectal cancers models.