LAUSR

Tumor evolution is driven by heterogeneity for heritable traits in combination with environmental selection forces including cancer therapies. We have been investigating intratumor cellular genetic and phenotypic heterogeneity in breast tumors and described that higher heterogeneity is associated with poor clinical outcomes. We have also developed experimental models of intratumor subclonal heterogeneity and demonstrated that more heterogeneous tumors grow faster and develop heterogeneous distant metastases. By analyzing the underlying mechanisms we defined that intratumor heterogeneity is maintained by non-cell-autonomous factors and clonal cooperation drives metastases by modulating the local and systemic microenvironments. Lastly, we have identified epigenetic enzymes as regulators of cellular transcriptomic heterogeneity and showed that by modulating the activity of these enzymes, we can decrease cellular heterogeneity and therapeutic resistance. Overall, our studies demonstrate the need to study cancer patients as a whole and to apply a combination of molecular profiling, including single cell assays, and mathematical modeling to understand how tumors evolved and to develop more effective cancer therapeutic strategies based on this knowledge. Citation Format: Kornelia Polyak. Tumor evolution: From Darwin’s finches to breast cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA26.