Abstract IA017: The polyaneuploid cancer cell state as a mediator of therapeutic resistance

Abstract

Abstract More than ten million people around the world will die from metastatic cancer in 2022. To date, no common genomic signature has been defined that can explain or identify which patients will develop lethal metastatic cancer. In all of these incurable patients lethal cancer independently evolves capacities for metastasis, avoidance of all cellular death pathways, and resistance. This convergent outcome demands an explanation beyond the slow and steady accrual of stochastic mutations. Generally, it is thought that cancer cells utilize the forces of natural selection when utilizing accumulating mutations during its evolution. Their utilization of heritable variation permits the cancer cell population to respond and survive environmental hazards. The tumor ecosystem is exposed to extreme and constantly changing chemical conditions. These changes can be natural, (e.g., loss of blood supply) or imposed (therapeutic). While the nature of these catastrophes may be varied or unique, their common property may be to doom the current cancer phenotype unless it evolves rapidly. We propose a complementary theory to explain cancer cell fitness through these environmental hazards that lead to metastasis, therapeutic resistance, and lethality. The basis of this theory is that a subset of cancer cells accesses evolutionary or developmental (evo/devo) stress survival programs that enable whole genome doubling (polyploidization) and cell cycle arrest. These stress survival programs are observed across the tree of life, from unicellular both prokaryotes and eukaryotes, such as Archaea, Bacteria, and yeast, to multicellular organism including plants and animals. In cancer, environmental stress and these stress programs result in cancer cell survival though a state of cell cycle arrest that is simultaneously polyploid and aneuploid. During this polyaneuploid cancer cell (PACC) state, cancer cells pause their cell cycle and protect the integrity of their DNA. This avoids the environmental stresses associated with the tumor microenvironment and metastatic cascade as well as the toxic effects of systemic therapy. In addition, by doubling their DNA and increasing their RNA and protein material, cancer cells in the PACC state have increased potential to develop further resistance mechanism to environmental stressors and otherwise toxic therapies. We have demonstrated that upon removal of stress, e.g., chemotherapy, cells in the PACC state undergo depolyploidization and generate resistant progeny. Thus, cells in the PACC state may play a critical role in lethality by their increased capacity to endure novel and stressful environments. This enables the metastatic phenotype and the generation of heritable variation that can be dispensed to their 2N+ aneuploid progeny, providing population rescue in response to therapeutic stress. Targeting cells in the PACC state is essential to cancer therapy and patient cure. Citation Format: Kenneth J. Pienta. The polyaneuploid cancer cell state as a mediator of therapeutic resistance [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 IA017.