RESUMEN
Cancer is a significant global health issue, with treatment challenges arising from intratumor heterogeneity. This heterogeneity stems mainly from somatic evolution, causing genetic diversity within the tumor, and phenotypic plasticity of tumor cells leading to reversible phenotypic changes. However, the interplay of both factors has not been rigorously investigated. Here, we examine the complex relationship between somatic evolution and phenotypic plasticity, explicitly focusing on the interplay between cell migration and proliferation. This type of phenotypic plasticity is essential in glioblastoma, the most aggressive form of brain tumor. We propose that somatic evolution alters the regulation of phenotypic plasticity in tumor cells, specifically the reaction to changes in the microenvironment. We study this hypothesis using a novel, spatially explicit model that tracks individual cells' phenotypic and genetic states. We assume cells change between migratory and proliferative 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. Notably, different genetic configurations can result in this pattern of phenotypic heterogeneity. We analytically predict the outcome of the evolutionary process, showing that it depends on the tumor microenvironment. Synthetic tumors display varying levels of genetic and phenotypic heterogeneity, which we show are predictors of tumor recurrence time after treatment. Interestingly, higher phenotypic heterogeneity predicts poor treatment outcomes, unlike genetic heterogeneity. Our research offers a novel explanation for heterogeneous patterns of tumor recurrence in glioblastoma patients.
Asunto(s)
Neoplasias Encefálicas , Movimiento Celular , Proliferación Celular , Glioblastoma , Fenotipo , Microambiente Tumoral , Humanos , Glioblastoma/genética , Glioblastoma/patología , Proliferación Celular/genética , Microambiente Tumoral/genética , Movimiento Celular/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Mutación , Heterogeneidad Genética , Biología Computacional , Neoplasias/genética , Neoplasias/patología , Modelos BiológicosRESUMEN
Moral rules allow humans to cooperate by indirect reciprocity. Yet, it is not clear which moral rules best implement indirect reciprocity and are favoured by natural selection. Previous studies either considered only public assessment, where individuals are deemed good or bad by all others, or compared a subset of possible strategies. Here we fill this gap by identifying which rules are evolutionary stable strategies (ESS) among all possible moral rules while considering private assessment. We develop an analytical model describing the frequency of long-term cooperation, determining when a strategy can be invaded by another. We show that there are numerous ESSs in absence of errors, which however cease to exist when errors are present. We identify the underlying properties of cooperative ESSs. Overall, this paper provides a first exhaustive evolutionary invasion analysis of moral rules considering private assessment. Moreover, this model is extendable to incorporate higher-order rules and other processes.