Abstract 125: The role of oxidative stress on the polyaneuploid cancer cell state in metastatic cancer

Abstract

Abstract Metastatic cancer is responsible for 90% of cancer deaths and is currently incurable due to resistance to all systemic anticancer therapies. Our lab hypothesizes that this resistance is driven by a subpopulation of cells in the tumor that enter the polyaneuploid cancer cell (PACC) state by undergoing a polyaneuploid transition (PAT). Cells in the PACC state are found in cell culture, xenograft, and genetically engineered mouse models, as well as in clinical samples. We have shown that cancer cells are induced to undergo a PAT upon exposure to external stress, such as chemotherapeutic treatments that include platinum-based therapy, etoposide, and taxane drugs. In addition, cells that enter the PACC state are resistant to that stress. One mechanism of therapy-induced cancer cell death is due to the resultant oxidative stress. We hypothesize that this oxidative stress drives a subset of cancer cells to undergo the PAT, thus enabling them to persist following treatment. To test the effects of oxidative stress on the PACC state, we treated cancer cells with cisplatin to induce the PAT and measured mitochondrial function and levels of reactive oxygen species (ROS). Using fluorescence microscopy with live-cell mitochondrial and ROS dyes, we showed that cells in the PACC state have higher mitochondrial mass, exhibit two to three times more mitochondrial activity per total mitochondria, and have over a five-fold increase in intracellular ROS levels per unit area when compared to typical cancer cell populations that they arise from. Moreover, PACCs exhibit a three-fold increase in their oxygen consumption rate and have higher expression of genes related to mitochondrial respiration and antioxidant pathways when compared to cells that did not undergo the PAT. Taken together, this suggests that cells in the PACC state may have a higher tolerance for stress since they can withstand higher amounts of ROS that result from both therapy and mitochondrial activity without exhibiting cell death. Our goal is to investigate how oxidative stress affects PACC formation and identify mechanisms of how PACCs manage stress to ultimately target these cells. If we can prevent PACC formation or find a method to eliminate cells in the PACC state, we can attack and resolve the issue of therapeutic resistance and incurability of metastatic cancer. Citation Format: Melvin Li, Sarah R. Amend, Kenneth J. Pienta. The role of oxidative stress on the polyaneuploid cancer cell state in metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 125.