Abstract 1991: Leiomyosarcoma poly-aneuploid cancer cells form in response to chemotherapy, contribute to chemoresistance, and lead to higher rates of metastatic recurrence
Authors: Ryan Kennington, Gareth Mitchell, Emily Payne, Niraja Bhachech, Jonathan A. Fletcher, Ting Liu, Matt van de Rijn, Sarah Amend, Kenneth J. Pienta, Joshua D. Schiffman, Lisa M. Abegglen
Journal: Cancer Research (2024)

Abstract Poly-aneuploid cancer cells (PACCs) or as also known as “giant cells”, are a treatment resistant stem cell-like cancer phenotype. PACCs have been identified in numerous cancer types, and their presence appears to play a significant role in chemoresistance and poor patient outcomes. PACCs employ a multitude of polyploidization programs to enter this transient state in response to stress. After removal of stress, PACCs give rise to non-PACC progeny through potential mechanisms of neosis or depolyploidization that maintain chemotherapeutic resistance. Leiomyosarcoma (LMS) is a difficult to treat sarcoma that grows in smooth muscle that often develops chemoresistance. Here we report the first description of PACCs in LMS cell culture, LMS xenografts, and LMS patient tumor microarrays. LMS cells treated (doxorubicin, docetaxel, and gemcitabine) in vitro and in vivo lead to the development of mononucleated and multinucleated polypoid cells as the predominant phenotype via polyploidization. Polyploidization mechanisms identified included endocycling, endomitosis, and cell-cell fusion. In vitro, LMS PACCs had a significant increase in size and DNA content as well as an increase in resistance to chemotherapy as compared to parents. LMS PACCs also repopulated the culture with non-PACC LMS progeny cells. The PACC progeny cells maintained a significantly decreased (p&amp;lt;0.0001) response to chemotherapy compared to parent cells. PACCs were also identified in clinical samples from patients with LMS. Twenty-nine percent of samples (N=289) contained abnormally large tumor cells and fifty-eight percent contained abnormal nuclei. A positive correlation was observed in patient tumor samples between PACCs in metastatic tumors and recurrence (p=0.0277) and survival (p=0.0009) than those patient tumors without PACCs. The high rate of functional loss of TP53 in LMS (&amp;gt;90%) may contribute to the ability of PACCs to form abnormal, multiple nuclei. We therefore transfected LMS PACCs to express TP53 and observed an increased apoptotic response. Additionally, combining functional TP53 expression with low doses of doxorubicin increases the apoptotic response of LMS cells, potentially by targeting PACCs. LMS PACCs may contribute to the lack of response in patients with LMS. Identifying therapeutic approaches that prevent or target LMS PACCs, including TP53 replacement, may improve response to chemotherapy and improve outcomes for patients. Citation Format: Ryan Kennington, Gareth Mitchell, Emily Payne, Niraja Bhachech, Jonathan A. Fletcher, Ting Liu, Matt van de Rijn, Sarah Amend, Kenneth J. Pienta, Joshua D. Schiffman, Lisa M. Abegglen. Leiomyosarcoma poly-aneuploid cancer cells form in response to chemotherapy, contribute to chemoresistance, and lead to higher rates of metastatic recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1991.