Cell Plasticity & Epigenetics

It is generally accepted that tumours are subjected to a myriad of evolutionary constraints at their niche of origin and further within the ecosystems encountered while invading novel tissues. Thus, evolutionary forces shape cancer development on many levels, as progression of the disease is often correlated with the appearance of somatic mutations and the selection of genetic traits that eventually become beneficial to neoplastic growth and often prejudicial to the host. Indeed, often-acquired mutations alter growth control systems and obliterate cell death programs, ultimately granting mutated cells with replicative immortality at the expense of genetic instability. However, due to the variable nature of the selective pressure in a particular niche, stable somatic mutations arise only after recurrent encounters with a challenging force. This suggests that, though under heavy evolutionary constraints, genetic changes driving adaptation do not occur immediately and highlights the biological relevance of cancer cell plasticity during neoplastic evolution.

Figure 1: Conceptual flow underlying our research lines.

A striking example that brings forward the plasticity of cancer cells is their resilience when confronted with therapeutic paradigms. Indeed it is acknowledged that, in response to sustained treatment, cancer cells may acquire genetic mutations that permanently block the tumouricidal action of the administered drug. However, in other settings, the emergence of fully drug-resistant clones cannot be explained by genetic mechanisms and results from cells that escape the initial death challenge by “adapting” to the pernicious agent. In the latter scenario, the traits granting adaptation to treatment are reversible in nature and are readily inherited through several cell divisions. This particularity strongly suggests the existence of a non-genetically encoded “temporal memory” underlying the acquisition of “drug-tolerant” phenotypes and represents an exquisite example of the transfer of non-genetic information through cell division. Along those lines, the ultimate goal of our lab is to unravel the network of molecular systems supporting cell plasticity and to shed light onto the core mechanisms underlying the inheritance of epigenetically encoded traits. We are currently setting up a multidisciplinary team that takes advantage of high-throughput sequencing and imaging technologies as well as more traditional molecular and cellular biology techniques to analyse the role of non-coding RNA molecules in the generation and propagation of epigenetic memories through subsequent cell divisions with particular interest in the acquisition of drug-tolerance in cancer relevant settings.