Abstract: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality with 46,420 new cases in 2014 in the USA; it is projected to surpass breast, prostate, and colorectal cancers as the second leading cause of cancer-related deaths by 2030 (Rahib et al., Cancer Res, 2014). Each year, over 80% of new cases are diagnosed as locally advanced or metastatic disease, and median survival is less than 6 months. The 5-year survival rate has remained around 3% for the past twenty-five years and is the lowest of any cancer. Therefore, PDAC remains one of the greatest challenges in cancer research. Signatures of genetic and molecular alterations in PDAC were identified. For example, mutational activation of Kras and inactivation of Ink4a/Arf are the most frequently identified genetic alterations in PDAC. Recent studies demonstrated that both mutant Kras and Ink4a are required for the development of PDAC in genetically engineered mouse models, thus indicating an essential role of Kras mutation in PDAC development. However, the mechanisms by which mutant Kras and Ink4a/Arf are required to initiate and maintain PDAC in mouse models and also coordinate reprogramming metabolism are not fully understood. Dysfunctional mitochondria and increased aerobic glycolysis are two prominent biochemical features frequently found in cancer cells. A metabolic shift from oxidative phosphorylation in the mitochondria to glycolysis in the cytosol in cancer cells has been well known for decades as ?the Warburg effect?. Recent studies also show that oncogenic Kras maintains the tumorigenic phenotype in PDAC through regulation of anabolic glucose metabolism. Although the reprograming of cellular metabolism is now recognized as a key event during tumorigenesis, the biochemical/molecular mechanisms responsible for this metabolic shift in PDAC cells remain elusive. Our preliminary results of the oncogenic function of mutant Kras and Ink4a/Arf in our experimental cell-based models have established groundwork in identifying the mechanisms of mutated Kras and Ink4a/Arf involved in reprogramming of cellular metabolism. We hypothesize that mutationally activated Kras and inactivated Ink4a/Arf coordinately activate the downstream signaling cascades to induce NOX4 activation for reprograming metabolisms. Therefore, the aims of the proposed research are to determine whether NOX4 is required to maintain the tumorigenic phenotype of PDAC, identify which are the essential downstream pathways regulating NOX4; and elucidate how NOX4 activation is regulated. Our findings will illuminate the mechanistic insights of the essential signaling pathways required for Kras/Ink4a-driven PDAC development, and identify the major molecular players involved in the metabolic shift in PDAC development.