Gain-of-function p53R175H blocks apoptosis in a precursor model of ovarian high-grade serous carcinoma

Jacob Haagsma; Bart Kolendowski; Adrian Buensuceso; Yudith Ramos Valdes; Gabriel E DiMattia; Trevor G Shepherd

doi:10.1038/s41598-023-38609-5

Gain-of-function p53^R175H blocks apoptosis in a precursor model of ovarian high-grade serous carcinoma

Sci Rep. 2023 Jul 14;13(1):11424. doi: 10.1038/s41598-023-38609-5.

Authors

Jacob Haagsma^{1

2}, Bart Kolendowski¹, Adrian Buensuceso^{1

2}, Yudith Ramos Valdes¹, Gabriel E DiMattia^{1

3

4}, Trevor G Shepherd^{5

6

7

8

9}

Affiliations

¹ The Mary and John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON, Canada.
² Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
³ Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁴ Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁵ The Mary and John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON, Canada. tshephe6@uwo.ca.
⁶ Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. tshephe6@uwo.ca.
⁷ Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. tshephe6@uwo.ca.
⁸ Department of Obstetrics and Gynaecology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. tshephe6@uwo.ca.
⁹ London Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, ON, N6A 4L6, Canada. tshephe6@uwo.ca.

Abstract

Ovarian high-grade serous carcinoma (HGSC) is a highly lethal malignancy for which early detection is a challenge and treatment of late-stage disease is ineffective. HGSC initiation involves exfoliation of fallopian tube epithelial (FTE) cells which form multicellular clusters called spheroids that colonize and invade the ovary. HGSC contains universal mutation of the tumour suppressor gene TP53. However, not all TP53 mutations are the same, as specific p53 missense mutants contain gain-of-function (GOF) properties that drive tumour formation. Additionally, the role of GOF p53 in spheroid-mediated spread is poorly understood. In this study, we developed and characterized an in vitro model of HGSC based on mutation of TP53 in mouse oviductal epithelial cells (OVE). We discovered increased bulk spheroid survival and increased anchorage-independent growth in OVE cells expressing the missense mutant p53^R175H compared to OVE parental and Trp53ko cells. Transcriptomic analysis on spheroids identified decreased apoptosis signaling due to p53^R175H. Further assessment of the apoptosis pathway demonstrated decreased expression of intrinsic and extrinsic apoptosis signaling molecules due to Trp53 deletion and p53^R175H, but Caspase-3 activation was only decreased in spheroids with p53^R175H. These results highlight this model as a useful tool for discovering early HGSC transformation mechanisms and uncover a potential anti-apoptosis GOF mechanism of p53^R175H.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cystadenocarcinoma, Serous* / pathology
Female
Gain of Function Mutation
Humans
Mice
Ovarian Neoplasms* / pathology
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Tumor Suppressor Protein p53

Grants and funding

175060/CIHR/Canada