Abstract 6055: Polyaneuploid cancer cells are metabolically active and utilize lipid droplets to survive toxic stress
Authors: Kostecka Laurie Gayle , Le Anne , Amend Sarah , Pienta Kenneth J. 
Published: April 2023

Over 30,000 men in the U.S. die from metastatic prostate cancer each year. Metastatic cancer remains incurable as a population of cancer cells within a tumor are resistant to all known therapies. Despite decades of research, the source of therapeutic resistance is still unknown. We have identified the polyaneuploid cancer cell (PACC) state as a chemo-resistant cell state that is associated with therapeutic resistance. Cells in the PACC state are large in size, have high genomic content, and represent the majority cell state following high dose chemotherapy in vitro. While the PACC state has been documented in patient samples of many cancer types, including prostate cancer where it is associated with progression, the survival mechanisms that enable the PACC state remain largely undefined. We discovered that cells in the PACC state are highly metabolically active and contain a higher number of lipid droplets (LDs) than the non-polyploid parental cells they are derived from. LDs act as central anti-lipotoxic organelles and sequestration of toxic moieties into LDs allows for lower lipotoxicity in cells and higher chances of survival and future proliferation. Higher levels of LDs are associated with increased tumor aggressiveness and chemotherapy resistance. We found that PLIN1 (an exclusive LD surface protein), and DGAT1 (an enzyme that catalyzes the generation of TAG, which is the main component of LDs) are expressed at higher levels in the tumors of prostate cancer patients with lower disease-free survival and higher Gleason score. This indicates that aggressive prostate cancer is most likely associated with high levels of LDs. We hypothesize that cells entering the PACC state survive chemotherapeutic stress by having an elevated metabolism and sequestering toxic lipids into LDs to enhance cell survival. Metabolomic and lipidomic data demonstrate that PACCs have a highly active TCA cycle and higher overall lipids in multiple classes compared to the parental cells they are derived from. Additionally, utilizing flow cytometry and imaging, we found that LDs form in cells accessing the PACC state as early as three hours post chemotherapy treatment, suggesting a crucial role for avoiding lipotoxicity. We also observed low levels of HSL (a rate limiting enzyme in lipolysis) in the PACC state indicating that after PACCs form LDs they do not immediately break them down, another possible mechanism of avoiding lipotoxicity. We have shown this in four cancer cell lines from two tumor types (Prostate cancer: PC3, DU145, and LNCaP. Breast cancer: MDA-MB-231) with three classes of chemotherapies (cisplatin, docetaxel, etoposide), proving the observed phenotype is not specific to any one cell line, tumor type, or drug class. Our future work will focus on inhibiting lipid droplet formation in vivo and in vitro to increase cellular lipotoxicity in the PACC state to induce cancer cell death.

Citation Format: Laurie Gayle Kostecka, Anne Le, Sarah Amend, Kenneth J. Pienta. Polyaneuploid cancer cells are metabolically active and utilize lipid droplets to survive toxic stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6055.