Abstract B015: Eco-evolutionary dynamics of poly-aneuploid cancer cells: A life history model

Abstract

Abstract Despite major advances in cancer research over the last several decades, advanced cancers largely remain incurable due to the evolution of resistance. Recent experimental evidence suggests that a poly-aneuploid cancer cell (PACC) state may contribute to the emergence of therapeutic resistance by allowing cancer cells to avoid the effects of and adapt to extreme environmental stressors. The PACC state is enabled when aneuploid cells undergo whole genome doubling but subsequently bypass mitosis, cytokinesis, or both. We create a novel mathematical framework for modeling the eco-evolutionary dynamics of state-structured populations and use this framework to construct a model of cancer populations with an aneuploid and a PACC state. Using in silico simulations, we explore how the PACC state allows cancer cells to 1) survive extreme environmental conditions by exiting the cell cycle after S phase and protecting genomic material and 2) aid in adaptation to environmental stressors by increasing the cancer cell's evolvability (ability to generate heritable variation) through the increase in genomic content that accompanies polyploidization. In doing so, we demonstrate the ability of the PACC state to contribute to therapeutic resistance and stress the importance of targeting PACC populations for improved therapeutic outcomes. Citation Format: Anuraag Bukkuri, Kenneth J. Pienta, Robert H. Austin, Emma U. Hammarlund, Sarah R. Amend, Joel S. Brown. Eco-evolutionary dynamics of poly-aneuploid cancer cells: A life history model [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B015.