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Stromal-mediated mitochondrial transfer promotes heterogeneity and metastasis in high-grade serous ovarian cancer

Frisbie, Leonard (2024) Stromal-mediated mitochondrial transfer promotes heterogeneity and metastasis in high-grade serous ovarian cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

High-Grade Serous Ovarian Cancer (HGSOC) is characterized by early and diffuse peritoneal spread, with most women presenting with extensive abdominal metastases during initial diagnosis. A major mediator of HGSOC progression and metastasis is the heterogeneity of cancer cells within a tumor, with increased diversity indicative of poorer outcomes in general. The surrounding non-malignant stromal tumor microenvironment plays an important role in modulating cancer cell heterogeneity although the mechanisms underlying this phenomenon remain poorly defined. Here, we demonstrate that patient-derived carcinoma-associated mesenchymal stem/stromal cells (CA-MSCs) enhance cancer cell heterogeneity both in vitro and in vivo through donation of their endogenous mitochondria. CA-MSC donation was found to preferentially occur to cancer cells displaying diminished metabolic function, enhancing their proliferative capacity, resistance to platin-based chemotherapy, and metabolic capacity. These findings were further validated in a fully autologous system using CA-MSCs and cancer cells derived from the same patient to prevent confounding effects of cellular response to foreign organelle/DNA. Targeting of the endogenous CA-MSC mitochondrial transport protein MIRO1 disrupted transfer to cancer cells and reversed the stromal-mediated rescue phenotype. Donor/recipient mitochondrial haplotype-specific qPCR measured persistence of CA-MSC mitochondrial DNA in recipient cancer cells up to day 14-post transfer. We further show receipt of CA-MSC-derived mitochondria drives secretion of pro-growth signaling factor ANGPTL3 by recipient cancer cells, which function to drive proliferation in non-recipient cancer cells in a paracrine fashion through MAPK activation. Significantly, CA-MSC mitochondrial donation was shown to occur in vivo and enhanced cancer cell heterogeneity and decreased overall survival in an orthotopic murine model. This work identifies CA-MSC-mediated mitochondrial transfer as a mediator of cancer cell heterogeneity through metabolic rescue and contributes to our broader understanding of how the stromal tumor microenvironment shapes HGSOC progression.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Frisbie, LeonardLGF7@pitt.eduLGF70000-0001-8996-4292
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorCoffman, Lan Gcoffmanl@upmc.edu
Committee ChairHempel, Nadinenah158@pitt.edu
Committee MemberLee, Adrianleeav@upmc.edu
Committee MemberBuckanovich, Ronaldbuckanovichrj@mwri.magee.edu
Committee MemberTaylor, Sarahtaylorse2@upmc.edu
Committee MemberZervantonakis, Ioannisioz1@pitt.edu
Date: 25 November 2024
Defense Date: 3 December 2024
Approval Date: 14 February 2025
Submission Date: 17 December 2024
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 92
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Integrative Systems Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Ovarian Cancer; Tumor Microenvironment; Mesenchymal Stem Cells; Organelle Trafficking; Metastasis
Date Deposited: 14 Feb 2025 15:19
Last Modified: 14 Feb 2025 15:19
URI: http://d-scholarship.pitt.edu/id/eprint/47299

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