Resolving translational challenges in cancer biology through yeast experimental evolution

Cancer genomics, molecular pathology, targeted therapy, and immunotherapy have transformed how tumors are diagnosed and treated, yet several problems remain hard to resolve prospectively, including the interpretation of variants of uncertain significance, variable penetrance, recurrent drug resistance, and the early trajectories that predispose later therapeutic failure. Many of these are fundamentally evolutionary questions about which adaptive routes are accessible under selection and how reproducibly they arise. Here, we make the case that yeast experimental evolution can serve cancer biologists as a practical upstream discovery platform, because its control, scale, and temporal resolution expose recurrent adaptive routes, transient intermediates, compensatory mechanisms, and genotype-to-fitness relationships that mammalian systems resolve only slowly. We organize representative studies by evolutionary dynamic, set out design principles and an operational workflow, and mark where these models are strong, where they mislead, and where fission yeast adds complementary strengths. Together, these elements frame yeast evolution as a way to prioritize and sharpen downstream validation in cancer systems.