Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths in the United States and is projected to become the second leading cause of cancer deaths by 2030. It is often undiagnosed until metastasized, and these advanced tumors display resistance to existing therapeutic modalities. Although there have been recent improvements in combination chemotherapies, the overall 5-year survival rate has not exceeded 8%. The lack of effective treatments and means of early detection necessitates the need to further dissect molecular mechanisms associated with PDAC progression in order to develop novel and effective therapeutic strategies and improve the survival rate of this lethal disease. Autophagy is the process in which cells degrade internal constituents for the maintenance of cellular homeostasis. It has been well documented that cancer cells induce autophagy as a survival mechanism in various malignancies including PDAC and is known to play a critical role in tumor progression and chemoresistance. Increasing evidence suggests the use of microRNA (miRNA) as a novel therapeutic agents for various human diseases including cancer. In our recent work, we found a significant downregulation of miR-29 in pancreatic cancer cells, and its restored expression sensitized chemotherapeutic resistant pancreatic cancer cell lines to gemcitabine, leading to reduced cancer cell viability and increased cytotoxicity. Furthermore, reintroduction of miR-29 in pancreatic cancer cells led to a blockage in autophagy by targeting ATG9A and TFEB, two genes critical for autophagosome trafficking and lysosomal function respectively. miR-29 overexpression in pancreatic cancer cell lines substantially decreased ATG9A and TFEB expression. Subsequent knockdown of ATG9A or TFEB expression alone or in combination resulted in inhibition of autophagy similar to miR-29 overexpression. Finally, miR-29 reduced migration, invasion, and anchorage independent growth of pancreatic cancer cells. Based on these observations, we hypothesize that miR-29 functions as a potent PDAC autophagy/invasion inhibitor, sensitizes cancer cells to gemcitabine, and can potentially be used to target PDAC. To test this hypothesis, we propose 1) To evaluate the effects of miR-29 on tumor response to gemcitabine and autophagy in vivo. 2) To identify upstream regulators of miR-29 in PDAC. We anticipate that the outcomes of this application will elucidate the pathophysiological role of miR-29 in PDAC autophagy and mechanisms for its downregulation.
Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States and is projected to become the second leading cause of cancer deaths by 2030. Although there have been recent improvements in combination chemotherapies, the overall 5-year survival rate has not exceeded 8%. The objective of this application is to help better understand molecular mechanisms of pancreatic cancer, and we expect that the results of this application will aid in developing novel and more effective treatments to reduce the morbidity and mortality associated with this lethal disease.
| Quirin, Kayla A; Kwon, Jason J; Alioufi, Arafat et al. (2018) Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice. Mol Ther Methods Clin Dev 8:8-20 |
