Abstract 3017: The poly-aneuploid cancer cell state utilizes lipid droplets as a mechanism of survival

Abstract

Abstract Cancer is the second leading cause of all death in the world, killing over 10 million people in 2020. Metastatic cancer is responsible for 90% of all cancer related deaths. Metastatic disease remains incurable as a population of cancer cells within a tumor are or become resistant to all known natural and synthetic therapies. Despite decades of research, the source of this therapeutic resistance still remains largely undefined. We have identified that the polyaneuploid cancer cell (PACC) transition state is associated with therapeutic resistance. This state of cells are large in size, have high genomic content, and are the only cell remaining in tissue culture conditions after high dose chemotherapy. The PACC transition state has been documented in many different cancer types but their survival mechanisms have remained largely unexplored. We have discovered that the PACC transition state contains a higher number of lipid droplets (LDs) than the parental cells they are derived from. LDs are central anti-lipotoxic organelles that control fatty acid, diacylglycerol, cholesterol, and ceramide lipotoxicity by sequestering toxic lipids into inert triglycerides, cholesterol esters, and acylceramides. LDs are important in cancer as higher levels of LDs are associated with higher tumor aggressiveness and chemotherapy resistance. Utilizing TCGA data we discovered that PLIN1, an exclusive LD surface protein, is higher in prostate cancer patients with lower disease-free survival, higher Gleason score, and higher tumor stage. This indicates that more aggressive prostate cancer, which has been shown to have a higher number of PACCs in patient samples, is associated with higher levels of LDs. We hypothesize that the PACC state is surviving chemotherapeutic stress by sequestering toxic lipids into LDs to enhance cell survival. To determine when and how LDs form in the PACC transition state we used live cell imaging, western blotting, flow cytometry, and staining of key lipid droplet proteins. We utilized four different cancer cell lines (PC3, DU145, LNCaP, MDA-MB-231) with three different classes of chemotherapies (cisplatin, docetaxel, etoposide). We established that LDs form in the PACC transition state as early as three hours post chemotherapy treatment. This suggests that the PACC state utilizes a key mechanism of sequestering toxic lipids into LDs as soon as therapy is applied to avoid lipotoxicity and cell death. We also discovered that hormone-sensitive lipase (HSL), an enzyme that mobilizes fats stored in LDs, was down in the PACC state compared to parental cells, indicating that these LDs are not readily being broken down after formation. Our future work will focus on inhibiting LD formation to increase cellular lipotoxicity in the PACC transition state leading to PACC death and an increase in overall cancer cells killed. Citation Format: Laurie Gayle Kostecka, Sarah Amend, Kenneth Pienta. The poly-aneuploid cancer cell state utilizes lipid droplets as a mechanism of survival [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 3017.