Carcinoma-associated mesenchymal stem cells promote ovarian cancer heterogeneity and metastasis through mitochondrial transfer
Leonard Frisbie,
Catherine Pressimone,
Emma Dyer,
Roja Baruwal,
Geyon Garcia,
Claudette St. Croix,
Simon Watkins,
Michael Calderone,
Grace Gorecki,
Zaineb Javed,
Huda I. Atiya,
Nadine Hempel,
Alexander Pearson,
Lan G. Coffman
Affiliations
Leonard Frisbie
Department of Integrative Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
Catherine Pressimone
School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Emma Dyer
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA
Roja Baruwal
Molecular Pharmacology Graduate Program, University of Pittsburgh, Pittsburgh, PA, USA
Geyon Garcia
School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Claudette St. Croix
Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA
Simon Watkins
Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA
Michael Calderone
Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA
Grace Gorecki
Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Zaineb Javed
Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Huda I. Atiya
Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Nadine Hempel
Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Alexander Pearson
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA; Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA
Lan G. Coffman
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; Corresponding author
Summary: 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.
