Dr Maximiliano Portal - Cell Plasticity & Epigenetics

Introduction

For decades the genome has been hailed as the major, if not the sole, evolutionary powerhouse of all of biology. However, compelling evidence obtained from various cellular systems and organisms suggest that complex networks of non-genetic information are equally fundamental in shaping evolution. Although, during the last decade the study of non-genetically encoded networks has seen a technology driven resurgence, the underlying molecular details encompassing how the genetic and non-genetic compartments crosstalk shape phenotypic output remain largely unknown. Notably, as evidenced by numerous examples scattered across the various areas of biology, including cancer, a cell phenotype is not exclusively determined by its genotype but is rather moulded by a multitude of non-genetic mechanisms encoded in complex dynamic networks. To mention a few, we can count DNA and histone modifications, high-order chromatin architecture, gene expression dynamics and RNA-protein interactions, amongst others of equal relevance; all of them acting in concert to bequest cells with the plasticity to thrive within an ever-changing environment.

It is in that context that phenotypic plasticity, the ability of a single genotype to produce a variety of phenotypes, has been documented as a core biological process underlying numerous molecular and cellular events ranging from unicellular adaptation to multi-cellular organism development. Translating this concept onto cancer cell populations, phenotypic plasticity may lead to the establishment of co-existing genetically identical cells yet harbouring phenotypically distinct metastable states that in turn, may endow tumour cells with the capability to adapt to fast-paced environmental conditions (exposure to anti-cancer drugs, hypoxia, invasion of new niches, etc).

Given the crucial role that non-genetically encoded phenotypic states play in biology, our research aims to unravel the molecular mechanisms underlying such a phenomenon and thrives to address its role as a key determinant in cell plasticity during cancer onset, progression and evolution. To do so, our lab blends the development and use of multimodal single cell technologies with the in-depth exploration of the basic biology underlying cell plasticity and populational heterogeneity in models of cellular proliferation, epithelial-to-mesenchymal transition, oncogene-induced transformation and resistance to anticancer drugs in 2D, 3D and organoid settings.

Following those lines, we have recently shown that in determined, fully differentiated cellular systems, non-genetic plasticity in terms of transcriptome diversity is not unlimited and/or random but is defined by the transcriptome states contained within its ancestry and their divergence, remarkably highlighting the existence of phylo(epi-)genetic lineages embedded within populations of genetically identical cells. Moreover, we have shown that the observed “restricted” plasticity correlates with the susceptibility of non-malignant cells to become tumourigenic upon oncogene activation and encompasses the adaptability of individual cancer cells to diverse extracellular challenges, including their response to anticancer therapeutic paradigms.

Given the profound relevance of our discoveries for most fields of biology, our lab is now moving forward into the decryption of the molecular devices regulating intra-populational lineage linked non-genetic plasticity and its crosstalk with genetic perturbations leading to cancer. We postulate that integrating these two crucial biological concepts – namely genetic and non-genetic information – and deciphering their interplay will drive forward our understanding of cancer evolution, which in turn would lead our discoveries into the design of more effective anticancer therapies.

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