Phenotypic switching and adaptive strategies of cancer cells in response to stress: insights from live cell imaging and mathematical modeling

Abstract

A major challenge in cancer therapy is drug resistance, which is typically attributed to acquired mutations and tumor heterogeneity. However, emerging evidence suggests that dynamic cellular interactions and group behavior also contribute to drug resistance, although, the details of such mechanisms are poorly understood. Here, by combining real time cellular growth data with mathematical modeling, we showed that the cisplatin-sensitive and tolerant lung cancer cells when co-cultured in cisplatin-free and cisplatin-treated environments, exhibit drastically different group strategies in response to environmental changes. While tolerant cells exhibited a persister-like behaviour and were attenuated by sensitive cells, sensitive cells learned to evade chemotherapy from tolerant cells when co-cultured. Further, tolerant cells could switch phenotypes to become sensitive, although high cisplatin concentrations suppressed this switching. Finally, switching cisplatin administration from continuous to intermittent suppressed the emergence of tolerant cells, suggesting that intermittent rather than continuous chemotherapy may result in better outcomes in lung cancer.