Characterizing the fibrogenic role of NADPH oxidase 1 in the transition from chronic pancreatitis to pancreatic cancer

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PROJECT SUMMARY/ABSTRACT The problem: Patients suffering from chronic pancreatitis (CP) have a higher risk of pancreatic ductal adenocarcinoma (PDAC). CP is characterized by an activated pancreatic stellate cell (PaSC)-rich stroma, which has facilitated the progression of non-invasive PanIN lesions to invasive PDAC. A critical barrier to progress in preventing the CP-to-PDAC transition is the gap of knowledge regarding the mechanism by which quiescent PaSCs become activated by inflammatory mediators, expand, and synthesize stroma and matrix metalloproteinases (MMPs), facilitating the progression of non-invasive PanIN lesions to invasive PDAC. Among the inflammatory mediators of CP are reactive oxygen species (ROS), which activate PaSCs. ROS generation can occur as a primary product of NADPH oxidase (Nox) enzymes. Previously, we showed that Nox1 signaling in CP-activated PaSCs: i) forms fibrotic tissue, ii) up-regulates both the transcription factor E-cadherin repressor Twist1 and MMP-9, and iii) facilitates the invasion of pancreatic cancer cell lines both in vitro and in vivo. The objective: To address the gaps in our knowledge regarding the mechanisms by which Nox1/Twist1/MMP-9 signaling in CP-activated PaSCs facilitates the progression of non-invasive PanIN lesions to invasive PDAC. The central hypothesis: The induction of CP generates ROS by Nox1 in PaSCs, which lead to a sustained expression of Twist1. Twist1, in turn, induces the expression of MMP-9, which promotes the progression of non- invasive PanIN lesions to invasive PDAC by degrading the basal lamina. The hypothesis will be tested by pursuing two specific aims: 1) Under the first aim, we will test in vitro the prediction that inhibiting Nox1/Twist1/MMP-9 signaling in CP-activated PaSCs attenuates the degradation of collagen IV and laminin. Under the second aim, we will test in vivo the prediction that inhibiting Nox1 signaling in CP-activated PaSCs prevents the progression of non-invasive PanIN lesions to invasive PDAC by attenuating the degradation of basal lamina. Our outcomes will include 1) new knowledge of CP-related mechanisms of progression of PDAC, 2) new knowledge of Nox1-related mechanisms of progression of PDAC, 3) high impact research experiences for undergraduate students. The approach is innovate because it will assess the extent to which the generation of Nox1-derived ROS from CP-activated PaSCs can facilitate the progression of non-invasive PanIN lesions to invasive PDAC. The proposed research is significant because a finding that the lack of Nox1 in CP-activated PaSCs prevents the progression of PanIN lesions to invasive PDAC by attenuating the degradation of basal lamina will establish the feasibility and premise for future translational research directed at developing rational, stroma-targeted therapies of early-stages of PDAC (e.g., carcinoma in situ) that, in combination with other approaches might lead to clinical strategies to increase the survival of patients. Moreover, these studies are designed to promote opportunities for a diverse undergraduate student participation providing them with exposure to hands-on experiments and close mentoring.