Cellular Plasticity and Adaptive Gene Regulation in Cancer

Abstract: The ability of cancer cells to consistently escape therapy remains a fundamental challenge for effective treatments. A longstanding debate in the field has centered on whether resistance arises primarily through genetic reprogramming or through cellular plasticity. Emerging evidence increasingly supports a “plasticity-first” model in which adaptive cellular states initially arise through a physiological response to environmental stress and are subsequently stabilized and extended by both epigenetic memory and genetic mutations. In this talk I will describe evidence that cancer cells can engage in an exploratory reprogramming of gene regulation as a means of adapting toward progressively resistant states. I will also offer our perspective on the mechanisms that drive this adaptive gene regulation, including stress-induced feedback responses, combinatorial regulatory networks, and systems for maintaining and recalling adaptive states. Finally, I will highlight the broader relevance of these mechanisms – extending beyond cancer to contexts such as inflammation and neurobiology – and the insights they offer into the origin and evolution of novel gene regulatory programs.