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 provide evidence that the dose and treatment duration together drive the resistance of ovarian cancer cells to targeted therapy along a trajectory of cellular adaptation, that we denote the ‘resistance continuum’. We report that gradual dose exposure and prolonged treatment promote a continuous increase in fitness, and show that this process is mediated by evolving transcriptional, epigenetic and genetic changes that promote multiple cell state transitions. The resistance continuum is underpinned by the assembly of gene expression programs and epigenetically reinforced stress response regulation. Using both in vivo and in vitro models, we found that this process involves widespread reprogramming of cell survival pathways, including interferon response, lineage reprogramming, metabolic rewiring and oxidative stress regulation. Together, the resistance continuum reveals the dynamic nature of cellular adaptation, and carries implications for cancer therapies, as initial exposure to lower doses primes cells over time for increased resistance to higher doses.
