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Talk Title:

Cellular plasticity and developmental constraints in tumorigenesis and drug resistance

Abstract:

Cellular plasticity is emerging as an important driving force underlying cancer progression and drug resistance. In this talk, I will discuss the concept of cancer cell states present in the tumor prior to treatment, as well as those that accompany resistance to increasing drug doses. In particular, I will discuss work published in our recent manuscript ‘Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment’ and recent developments in this project. Second, I will discuss our new work of ‘Drug-induced adaptation along a resistance continuum in cancer cells’. In this work we demonstrate that resistance develops through trajectories of cell state transitions accompanied by a progressive increase in cell fitness, which we denote the ‘resistance continuum’. This cellular adaptation involves a step-wise assembly of gene expression programs and epigenetic reinforcement of cell states. These processes are underpinned by phenotypic plasticity/dedifferentiation, physiological adaptation to stress and metabolic reprogramming. Our results support the notion that stemness programs, commonly viewed as a proxy for phenotypic plasticity, enable adaptation, rather than providing a proximal resistance mechanism. Through systematic genetic perturbations, we identify an acquisition of progressive metabolic dependencies, exposing a spectrum of vulnerabilities that can be potentially exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell state transitions.