Abstract 1686: Leiomyosarcoma poly-aneuploid cancer cells form in response to chemotherapy and contribute to chemoresistance

Abstract

Abstract Poly-aneuploid cancer cells (PACCs) are large, treatment resistant cancer cells identified in a number of different cancer types, sometimes called “giant cells.” PACCs have stem cell-like phenotypes and appear to play a role in treatment resistance that leads to poor patient outcomes. The PACC phenotype is a transient state that cancer cells can adopt to protect themselves from stress. PACCs can give rise to non-PACC progeny that maintain resistance to chemotherapy. While PACCs are documented in many cancer types, they have not yet been documented in sarcoma. However, we identified PACCs in cell culture from leiomyosarcoma (LMS) patient tumors. The goal of this study was to characterize PACCs in LMS in vitro, in vivo, and in patient samples. When LMS cells grown in vitro or in mice were treated with chemotherapy (doxorubicin, gemcitabine, or docetaxel), large cells with atypical nuclei emerged as the predominant cellular phenotype. In vitro, these LMS PACCs were more resistant to chemotherapy and repopulated the culture with non-PACC LMS cells, potentially through a process called neosis. PACCs were also identified in clinical samples from patients with LMS. Current efforts are underway to test for a correlation between the amount of PACCs in patient samples and initial response to therapy, as well as long-term patient outcomes. LMS tumors often do not respond to chemotherapy so defining the role of PACCs in LMS may have important clinical implications. LMS PACCs, which are non-dividing cells, may contribute to the lack of response. Identifying therapeutic approaches that target and kill LMS PACCs may improve response to chemotherapy and improve outcomes for patients. LMS tumors have a very high rate of TP53 loss of function reported to be >90%; TP53 loss may contribute to the ability of these giant cells to form with such abnormal nuclei. LMS PACCs transfected to express functional TP53 undergo apoptosis. Additionally, combining functional TP53 expression with low doses of doxorubicin increases the apoptotic response of LMS cells, potentially by targeting PACCs. Ongoing investigations may support the development of effective TP53 based therapeutics to target PACCs and to improve outcomes for LMS patients. Citation Format: Lisa M. Abegglen, Niraja Bhachech, Gareth Mitchell, Ryan Kennington, Brad Nelson, Miranda Sharp, Matthew Buccilli, Anthony Iovino, Aarushi Rohaj, Jonathan A. Fletcher, Ting Liu, Matt van de Rijn, Sarah R. Amend, Kenneth J. Pienta, Joshua D. Schiffman. Leiomyosarcoma poly-aneuploid cancer cells form in response to chemotherapy and contribute to chemoresistance [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 1686.