Abstract 1565: USP13 influences metastatic features in fallopian tube-originated high-grade serous carcinoma

Abstract

Abstract High-grade serous ovarian carcinoma (HGSOC), originating from the fallopian tube, stands as a formidable challenging gynecologic malignancy with the highest mortality rate worldwide. Ubiquitin-specific peptidase 13 (USP13) has garnered attention due to the highly frequent USP13 gene copy amplification in human ovarian cancer. However, its precise pathological role in ovarian cancer remained elusive. To uncover the underlying role of USP13 in HGSOC, we developed a novel genetically engineered mouse model (GEMM) of HGSOC. Ovgp1-iCreERT2;Trp53flox/flox;Ptenflox/flox mouse (OPT) was crossed with Rosa26−LSL-Usp13 knockin mouse model (U), generating Ovgp1-iCreERT2;Trp53flox/flox;Ptenflox/flox ; Rosa26−LSL-Usp13 mouse model (OPTU). Usp13 overexpression with loss of p53 and Pten was induced specifically in fallopian tube secretory epithelial cells in OPTU mice. OPTU mice demonstrated the development of STIC and early HGSOC in the fallopian tube as well as invasive metastatic HGSOC. While OPT tumors largely retained mucinous and HGSOC subtypes, displaying limited metastatic behavior, OPTU tumors exhibited more complex ovarian tumor subtypes, including mucinous, HGSOC, and Mixed Mesodermal Mullerian Tumor (MMMT) histology. Furthermore, OPTU tumors showed invasive and metastatic phenotypes, characterized by an increased incidence of ovary invasion, metastasis to distant organs, and ascites development. Importantly, OPTU-driven HGSOC tumors closely resemble human HGSOC histology features, making the OPTU model a valuable tool for exploring fallopian tube-originated ovarian cancer. Primary ovarian cancer cells established from ascites of the OPTU mouse reproduced metastatic HGSOC tumorigenesis in the syngeneic mouse study. Stable USP13 knockdown in OPTU cells exhibited reduced cell proliferation and metastatic abilities in 2D and 3D cultures. In summary, this study underscores the pivotal role of USP13 in facilitating metastasis in fallopian tube-originated HGOSC. Our findings may provide a promising avenue for future therapeutic strategies aimed at mitigating the aggressive nature of USP13-amplified fallopian tube-originated HGOSC. Citation Format: Boram Mok, Juntae Kwon, Jinmin Zhang, Samuel Allsup, Hyeongjwa Choi, Cecil Han. USP13 influences metastatic features in fallopian tube-originated high-grade serous carcinoma [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 1565.