Evolution of phenotypic plasticity leads to tumor heterogeneity with implications for therapy

SimonSyga

TUD Dresden University of Technology

"Evolution of phenotypic plasticity leads to tumor heterogeneity with implications for therapy"

Cancer is a significant global health issue, with treatment challenges arising from intratumor heterogeneity. This study examines the complex relationship between somatic evolution and phenotypic plasticity, explicitly focusing on the interplay between cell migration and proliferation [1]. We propose that evolution does not act directly on phenotypic traits, like the proliferation rate, but on the phenotypic plasticity in response to the microenvironment [2]. We study this hypothesis using a novel, spatially explicit model that tracks individual cells' phenotypic and genetic states. We assume cells change between mobile and growing states controlled by inherited and mutation-driven genotypes and the cells' microenvironment. We observe that cells at the tumor edge evolve to favor migration over proliferation and vice versa in the tumor bulk. However, this phenotypic heterogeneity can be realized by distinct regulations of the phenotypic switch, which depend on the apoptosis rate and the cells' ability to sense their environment. Emerging synthetic tumors display varying levels of heterogeneity, which we show are predictors of the cancer's recurrence time after treatment. Interestingly, higher phenotypic heterogeneity predicts poor treatment outcomes, unlike genetic heterogeneity. [1] Hatzikirou, H. et al. (2010). 'Go or Grow': the key to the emergence of invasion in tumour progression? Math. Med. Biol., 29(1), 49-65. [2] Syga S. et al. (2024) Evolution of phenotypic plasticity leads to tumor heterogeneity with implications for therapy. PLOS Comput. Biol. 20(8): e1012003.
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