Exosomes as mediators of platinum resistance in ovarian cancer
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Jennifer Crow1, Safinur Atay1, Samagya Banskota1,2, Brittany Artale3, Sarah Schmitt1, Andrew K. Godwin1,4
1Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS
2Department of Biomedical Engineering, Duke University, Durham, North Carolina, NC
3Bioengineering Graduate Program, University of Kansas, Lawrence, KS
4University of Kansas Cancer Center, Kansas City, KS
Andrew K. Godwin, email: [email protected]
Keywords: ovarian cancer, EMT, exosomes, platinum-resistance, SMAD4
Received: June 29, 2016 Accepted: December 16, 2016 Published: January 02, 2017
Exosomes have been implicated in the cell-cell transfer of oncogenic proteins and genetic material. We speculated this may be one mechanism by which an intrinsically platinum-resistant population of epithelial ovarian cancer (EOC) cells imparts its influence on surrounding tumor cells. To explore this possibility we utilized a platinum-sensitive cell line, A2780 and exosomes derived from its resistant subclones, and an unselected, platinum-resistant EOC line, OVCAR10. A2780 cells demonstrate a ~2-fold increase in viability upon treatment with carboplatin when pre-exposed to exosomes from platinum-resistant cells as compared to controls. This coincided with increased epithelial to mesenchymal transition (EMT). DNA sequencing of EOC cell lines revealed previously unreported somatic mutations in the Mothers Against Decapentaplegic Homolog 4 (SMAD4) within platinum-resistant cells. A2780 cells engineered to exogenously express these SMAD4 mutations demonstrate up-regulation of EMT markers following carboplatin treatment, are more resistant to carboplatin, and release exosomes which impart a ~1.7-fold increase in resistance in naive A2780 recipient cells as compared to controls. These studies provide the first evidence that acquired SMAD4 mutations enhance the chemo-resistance profile of EOC and present a novel mechanism in which exchange of tumor-derived exosomes perpetuates an EMT phenotype, leading to the development of subpopulations of platinum-refractory cells.
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