A Role of Dynamin-related Protein 1 in Pancreatic Ductal Adenocarcinoma
Nagdas, Sarbajeet, Microbiology - School of Medicine, University of Virginia
Kashatus, David, MD-MICR Microbiology, University of Virginia
Bauer, Todd, MD-SURG Surgery, Admin, University of Virginia
Pancreatic ductal adenocarcinoma is the third-leading cause of cancer-related deaths in the United States. Even more harrowing, pancreatic cancer is one of the few cancers with projected increases in cancer-related deaths in the near future due to the combination of low 5-year survival rates of roughly 9% and expected increases in incidence rates. Molecularly, pancreatic cancer is best defined by the near universal presence of an oncogenic mutation in KRas and activation of the MAPK signaling pathway. Aberrant activation of Ras and the MAPK pathway drives many of the hallmarks of cancer, most classically increased cellular proliferation. Despite the field’s appreciation of numerous aspects of Ras- and MAPK-driven biology in pancreatic cancer, sparingly few MAPK targeted therapeutics have demonstrated efficacy in patients. Accordingly, there are limited therapeutic options for treatment of pancreatic cancer beyond surgery and chemotherapy. Together these facts highlight the need to better understand the molecular and cellular biology of pancreatic ductal adenocarcinoma to better inform the development of novel therapeutic approaches.
Of interest for our lab, mitochondria- in particular mitochondrial dynamics- are central in many of the physiologic changes associated with Ras-driven tumorigenesis such as increased cell proliferation, evasion of apoptosis, and altered cellular metabolism. Other groups had previously demonstrated that fragmented mitochondrial morphology was associated with tumorigenic phenotypes and that inhibiting Drp1, the large GTPase responsible for mitochondrial fragmentation, inhibited tumorigenesis. Indeed, our lab has previously demonstrated that HRas via the MAPK pathway phosphorylates and activates Drp1 that promotes mitochondrial fragmentation and that inhibition of Drp1 inhibited HRas-driven tumor growth. However the previous work demonstrating the importance of Drp1 in tumorigenesis, Ras-driven and otherwise, were done in systems lacking physiologic relevance not only to pancreatic ductal adenocarcinoma but also to in vivo tumorigenesis. Furthermore, the functional role of Drp1 in Ras-driven tumorigenesis was unexplored in our previous work, leaving a gap in our knowledge about the role of Drp1 in KRas-driven pancreatic cancer. To that end, this work aimed to use both in vitro and in vivo model systems of pancreatic ductal adenocarcinoma to determine the physiological role of Drp1 in pancreatic cancer tumorigenesis.
The work presented in this dissertation demonstrates that Drp1 acts to promote pancreatic ductal adenocarcinoma in part through modulation of distinct aspects of cellular metabolism. Specifically we show that Drp1 promotes KRas-driven tumorigenesis through direct modulation of glycolytic metabolism in murine and human systems. Drp1 is required for KRas-driven anchorage-independent growth in murine fibroblasts and patient-derived pancreatic cancer cell lines and the inhibition of Drp1 in these cells impairs glycolytic flux, in part through the downregulation of hexokinase 2 (HK2). Furthermore, deletion of Drp1 imparts a significant survival advantage in a genetically engineered mouse model of KRas-driven pancreatic cancer. In addition, KRas-driven tumors exhibit a strong selective pressure against complete deletion of Drp1. Rare tumors that arise in the complete absence of Drp1 have restored glycolysis, but exhibit defective mitochondrial metabolism and are unable to effectively utilize fatty acids as a fuel source. Thus, this work demonstrates that Drp1 plays dual roles in KRas-driven tumor growth: supporting glycolysis early in tumorigenesis and maintaining mitochondrial function throughout tumorigenesis. Collectively, the data presented in this dissertation and the literature indicate that Drp1 promotes KRas-driven tumorigenesis by regulating both mitochondrial and extra-mitochondrial metabolism, not only identifying Drp1 as a potential therapeutic target but also unveiling potential metabolic vulnerabilities in pancreatic ductal adenocarcinoma.
PHD (Doctor of Philosophy)
Mitochondria, Pancreatic Cancer, Cancer Metabolism
All rights reserved (no additional license for public reuse)