Tumor Heterogeneity\nShapes Survival Dynamics in Drug-Treated\nCells, Revealing Size-Drifting Subpopulations

The goal of this project was to demonstrate that subpopulations\nof cells in tumors can uniquely fluctuate in size in response to environmental\nconditions created during drug treatment, thereby acting as a dynamic\n“rheostat” to create a favorable tumor environment for\ngrowth. The cancer modeling used for these studies was subpopulations\nof melanoma cells existing in cultured and tumor systems that differed\nin aldehyde dehydrogenase (ALDH) activity. However, similar observations\nwere found in other cancer types in addition to melanoma, making them\napplicable broadly across cancer. The approach was designed to show\nthat either ALDH<sup>high</sup> and ALDH<sup>low</sup> subpopulations\nrapidly epigenetically transition between stem-cell-like high into\nnonstem-like low production states to create an environment during\ndrug treatment that would enable optimal cellular proliferation and\ntumor expansion to facilitate drug resistance. The controlled experiments\nshowed proportional changes in each cell population to reach an evolutionarily\nstable equilibrium mediated by the needed levels of ALDH enzyme activity.\nMechanistically, cell population size changes served to functionally\nmove the aldehyde and the resulting reactive oxygen species (ROS)\nlevels to those compatible with optimal cellular proliferation with\npopulation fluctuations dependent on the levels of drug induced tumor\nstress. This is the first report documenting fluctuations in the sizes\nof cell populations in tumors to cooperatively assist in drug resistance\ndevelopment.