Carcinoma-associated mesenchymal stem cells promote ovarian cancer heterogeneity and metastasis through mitochondrial transfer.

Cell Rep

Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Published: August 2024

Ovarian cancer is characterized by early metastatic spread. This study demonstrates that carcinoma-associated mesenchymal stromal cells (CA-MSCs) enhance metastasis by increasing tumor cell heterogeneity through mitochondrial donation. CA-MSC mitochondrial donation preferentially occurs in ovarian cancer cells with low levels of mitochondria ("mito poor"). CA-MSC mitochondrial donation rescues the phenotype of mito poor cells, restoring their proliferative capacity, resistance to chemotherapy, and cellular respiration. Receipt of CA-MSC-derived mitochondria induces tumor cell transcriptional changes leading to the secretion of ANGPTL3, which enhances the proliferation of tumor cells without CA-MSC mitochondria, thus amplifying the impact of mitochondrial transfer. Donated CA-MSC mitochondrial DNA persisted in recipient tumor cells for at least 14 days. CA-MSC mitochondrial donation occurs in vivo, enhancing tumor cell heterogeneity and decreasing mouse survival. Collectively, this work identifies CA-MSC mitochondrial transfer as a critical mediator of ovarian cancer cell survival, heterogeneity, and metastasis and presents a unique therapeutic target in ovarian cancer.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420855PMC
http://dx.doi.org/10.1016/j.celrep.2024.114551DOI Listing

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