Pancreatic ductal adenocarcinoma (PDA) is the fourth lethal cancer in the U.S. with a 5-year survival rate of only ~10%. The mainstay of therapy in PDA is chemotherapy, however, the majority of the tumors rapidly develop treatment resistance. Therefore, a critical need exists to understand what drives the emergence of drug resistance in PDA, and to develop better treatment strategies. One contributing factor to drug resistance in PDA is the tumor microenvironment, which is characterized by abundant stroma, rich in extracellular matrix (ECM) proteins, most frequently secreted by cancer-associated fibroblasts. The stroma and the secreted ECM proteins can induce resistance towards chemotherapies, which work by inflicting DNA damage. One way for the stroma to induce chemo-resistance would be by enhancing DNA repair. Our data show that the cancer- associated fibroblast-secreted ECM proteins stimulate DNA repair in PDA tumor cells, making them more resistant to treatments. The overall objective of this application is to investigate the mechanistic basis by which the tumor microenvironment, and particularly secreted stromal and ECM proteins, stimulate DNA repair. Our central hypothesis is that the candidate protein we have identified, called N-Myc-Downstream Regulated Gene 1 (NDRG1), conveys signals from the ECM contact to the DNA repair machinery, and our preliminary data support this hypothesis. To test this hypothesis further, we propose the following three specific aims: 1) to determine the detailed signaling events by which secreted ECM proteins lead to NDRG1 activation; 2) to determine the mechanism by which NDRG1 regulates DNA repair; and 3) to assess the efficacy of NDRG1- pathway inhibition in enhancing chemotherapy in patient-derived organoids and in vivo models of pancreatic cancer. The research proposed here is innovative, in our opinion, because the research on chemoresistance and DNA repair has not been studied in the context of adhesion signaling and stromal microenvironment, nor has the protein we propose to study here, NDRG1, been linked to DNA repair. Therefore, successful completion of this work would lead to a more complete mechanistic understanding on how tumor-stroma cross- talk and fibroblast-secreted matrix proteins regulate DNA repair, and how NDRG1 protein contributes to DNA repair and treatment resistance. These contributions are expected to be significant because they reveal novel DNA repair biology that is regulated by extracellular matrix environment in one of the most lethal, stroma rich and drug resistant cancers, and will allow us to test whether targeting this signaling pathway will enhance chemotherapy efficacy.
The proposed research is relevant to public health because it focuses on finding more effective treatment strategies for pancreatic cancer, one of the most lethal cancers, with a five year survival rate of only ~10%. Pancreatic cancer is extremely aggressive and responds very poorly to existing treatments, this is partially because of the tumor microenvironment that makes tumors more resistant to therapies. Our laboratory studies how this environment induces drug resistance, particularly by enhancing DNA repair, and we have identified novel drivers of resistance that we will target to develop new improved therapies for pancreatic cancer, reducing mortality.
