OCT 12, 2017 10:30 AM PDT

Hypersecretion of fibroblast-derived exosomes during chemotherapy promotes pancreatic cancer chemoresistance

Speaker
  • Archibald Assistant Professor of Cancer Biology, Department of Biological Sciences, Harper Cancer Research Institute, University of Notre Dame
    Biography
      I grew up in Cincinnati, Ohio where I found myself drawn to science even at a young age. I attended Florida A&M University and obtained a B.S. in Biology with a focus in Molecular Biology. During the summers I had opportunities to gain research experience through internships at USUHS, Pfizer, and the Genetics Institute. These experiences increased my desire to learn more about the mechanisms underlying disease progression.

      I continued my education at UNC-Chapel Hill by obtaining a PhD in Genetics and Molecular Biology in the lab of Terry Van Dyke, where I designed and created a new transgenic mouse model of prostate cancer that demonstrated the important role the microenvironment plays in tumor progression. As a Damon Runyon postdoctoral fellow with Dr. Hong Wu at UCLA, I chose to focus on pancreatic adenocarcinoma (PDAC), an under-researched disease with a high mortality rate, poor prognosis, and few therapeutic options. I developed mouse models to recapitulate the complexities of human PDAC in order to uncover new therapeutic strategies that could be translated to the human disease.

      My lab utilizes genetic models to address fundamental questions about how cell autonomous (e.g. genetic alteration) and cell non-autonomous (e.g. inflammation) mechanisms affect pancreatic cancer development. My focus is to uncover the central mechanisms through which the microenvironment aids tumor initiation, progression, and therapeutic resistance. A better understanding of these processes will not only help the development of more effective treatments for pancreatic cancer, but can be expanded to applications in a wide range of other diseases.

    Abstract

    Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of only 9%. Acquired drug resistance is a major factor that limits the effectiveness of chemotherapy. Exosomes, secreted membrane vesicles that range in size from 30–100 nm in diameter, released from epithelial cancer cells can promote drug resistance. However fibroblasts, not epithelial cells, make up the majority of the tumor bulk in PDAC. Despite the long-standing recognition of the prominence of the fibroblasts in PDAC, the mechanisms through which fibroblast-derived exosomes may contribute to chemoresistance following exposure to chemotherapy have not been studied. A molecular-level understanding of possible fibroblast-driven mechanisms of chemoresistance is essential for the development of more effective treatment strategies.

    Here, we show that CAFs exposed to chemotherapy play an active role in regulating the survival and proliferation of cancer cells through the hypersecretion of chemoresistance-promoting exosomes. We found that CAFs exposed to gemcitabine (GEM), the most widely used adjuvant therapy for PDAC, increase the release of exosomes. We utilized miRNA-SEQ analysis to identify miRs that were significantly increased in the exosomes of GEM-treated CAFs compared to treatment naïve CAFs and WT pancreatic fibroblasts. Five out of the top 10 hits were miRs that target PTEN. We utilized GW4869, a compound that inhibits exosome secretion, to functionally show in vitro and in vivo that blocking exosome release from GEM-treated CAFs reduces chemotherapy resistance in PDAC cells through restoration of PTEN expression. Collectively, these findings elucidate the role of CAF-derived exosomes in regulating PDAC chemoresistance and suggest that therapeutic strategies design to inhibit exosome release may lead to improved patient response.


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