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Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells

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Abstract

Cancer-associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic ductal adenocarcinomas (PDACs). Current efforts to eradicate these tumors focus predominantly on targeting the proliferation of rapidly growing cancer epithelial cells. We know that this is largely ineffective with resistance arising in most tumors following exposure to chemotherapy. Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of chemotherapy on CAFs and how they may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that CAFs exposed to chemotherapy have an active role in regulating the survival and proliferation of cancer cells. We found that CAFs are intrinsically resistant to gemcitabine, the chemotherapeutic standard of care for PDAC. Further, CAFs exposed to gemcitabine significantly increase the release of extracellular vesicles called exosomes. These exosomes increased chemoresistance-inducing factor, Snail, in recipient epithelial cells and promote proliferation and drug resistance. Finally, treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly reduces survival in co-cultured epithelial cells, signifying an important role of CAF exosomes in chemotherapeutic drug resistance. Collectively, these findings show the potential for exosome inhibitors as treatment options alongside chemotherapy for overcoming PDAC chemoresistance.

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Acknowledgements

We acknowledge Dr Robert Stahelin of the Indiana University School of Medicine for generously allowing us to use his particle analyzer and ultracentrifuge, Dr Niranjan Awasthi of the Indiana University School of Medicine–South Bend for helpful discussions and Dr Steven Ruggiero of the University of Notre Dame for allowing us to perform light transmission spectroscopy in his lab. This research was funded by the Indiana CTSI and Harper Cancer Research Institute of Notre Dame.

Financial Information: R Hill was awarded financial support from the Walther Cancer Foundation and the Joseph D Boyle Memorial Fund. Work by ML Fishel was supported by grants from the National Institutes of Health, NCI CA167291, with additional support from the Biomedical Research Grant and in part by Jeff Gordon Children’s Foundation.

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Authors and Affiliations

  1. Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA

    K E Richards, A E Zeleniak & R Hill

  2. Department of Biological Sciences, Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA

    K E Richards, A E Zeleniak, J Wu, L E Littlepage & R Hill

  3. Integrated Biomedical Sciences Program, University of Notre Dame, South Bend, IN, USA

    A E Zeleniak, L E Littlepage & R Hill

  4. Department of Pediatrics, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA

    M L Fishel

  5. Department of Pharmacology, Indiana University, Indianapolis, IN, USA

    M L Fishel

  6. Indiana University Simon Cancer Center, Indianapolis, IN, USA

    M L Fishel, L E Littlepage & R Hill

  7. Department of Toxicology, Indiana University, Indianapolis, IN, USA

    M L Fishel

  8. Department of Chemistry, University of Notre Dame, Notre Dame, IN, USA

    J Wu & L E Littlepage

  9. Department of Biochemistry, University of Notre Dame, Notre Dame, IN, USA

    J Wu & L E Littlepage

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  1. K E Richards
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Correspondence to R Hill.

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Richards, K., Zeleniak, A., Fishel, M. et al. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene 36, 1770–1778 (2017). https://doi.org/10.1038/onc.2016.353

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  • DOI: https://doi.org/10.1038/onc.2016.353

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