Tumor Heterogeneity Shapes Survival Dynamics in Drug-Treated Cells, Revealing Size-Drifting Subpopulations.

Abstract

The goal of this project was to demonstrate that subpopulations of cells in tumors can uniquely fluctuate in size in response to environmental conditions created during drug treatment, thereby acting as a dynamic "rheostat" to create a favorable tumor environment for growth. The cancer modeling used for these studies was subpopulations of melanoma cells existing in cultured and tumor systems that differed in aldehyde dehydrogenase (ALDH) activity. However, similar observations were found in other cancer types in addition to melanoma, making them applicable broadly across cancer. The approach was designed to show that either ALDH^high and ALDH^low subpopulations rapidly epigenetically transition between stem-cell-like high into nonstem-like low production states to create an environment during drug treatment that would enable optimal cellular proliferation and tumor expansion to facilitate drug resistance. The controlled experiments showed proportional changes in each cell population to reach an evolutionarily stable equilibrium mediated by the needed levels of ALDH enzyme activity. Mechanistically, cell population size changes served to functionally move the aldehyde and the resulting reactive oxygen species (ROS) levels to those compatible with optimal cellular proliferation with population fluctuations dependent on the levels of drug induced tumor stress. This is the first report documenting fluctuations in the sizes of cell populations in tumors to cooperatively assist in drug resistance development.