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(Unpublished)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