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

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. [Display omitted] •CA-MSCs donate mitochondria to ovarian cancer cells with low endogenous mitochondria•Mitochondrial donation enhances cancer cell proliferation, chemoresistance, and OXPHOS•Donated mito-to-nuclear signaling drives ANGPTL3 secretion, which increases tumor cell growth•Mito donation enhances metastasis and clonal heterogeneity in vivo Frisbie et al. demonstrate that stromal-to-tumor cell mitochondrial transfer drives ovarian cancer metastasis and clonal heterogeneity. Carcinoma-associated mesenchymal stem cells donate mitochondria to vulnerable tumor cells, enhancing tumor cell proliferation, chemoresistance, and respiratory capacity and triggering ANGPTL3 secretion to further promote tumor growth. These findings offer a potential therapeutic target for ovarian cancer.