Project Summary: Early systemic dissemination, extraordinary local invasion, late diagnosis, and inadequate response to the existing chemotherapy contribute to poor prognosis for pancreatic cancer patients. There is an urgent need to identify novel therapies that would significantly improve survival in patients. While most pancreatic ductal adenocarcinomas have mutations in Kras, multiple other genetic alterations contribute to molecular oncogenesis and patient prognosis. These genetic lesions hold the key to novel personalized therapies for pancreatic cancer patients but remain poorly explored. Identifying novel personalized therapeutic combinations would be a significant advancement in combating PDAC. We and others identified a novel ME2 deletion as a passenger deletion with SMAD4 loss, which is prevalent in up to 30% of PDAC patients. By utilizing cell culture models, organoids, orthotopically-implanted mouse models, and patient-derived xenografts of pancreatic ductal adenocarcinoma with and without ME2-loss, we made the novel observation that ME2 has a direct negative impact on tumor growth and metastasis in pancreatic cancer. Here, we propose to investigate the molecular basis of ME2 loss-mediated oncogenesis in pancreatic cancer. By utilizing a series of unbiased high-throughput screening approaches, we have identified novel signaling alterations in pancreatic cancer cells due to ME2 loss. Hence, we will also investigate the effectiveness of blocking the signaling pathways induced by the ME2 loss that facilitate aggressiveness in pancreatic cancer. Such mechanisms potentially regulate tumor cell growth and invasiveness of low ME2-expressing tumor cells. Thus, our studies will facilitate the development of new and more effective treatments for pancreatic cancer. Our long-term goal is to determine the molecular basis of ME2 loss-mediated signaling that facilitates invasiveness and metastasis in pancreatic cancer. In the first aim, we will utilize genetically engineered mice models to investigate the impact of ME2 loss on pancreatic cancer initiation, progression, and metastasis. The second aim will investigate the molecular basis of ME2 loss-mediated aggressiveness in pancreatic cancer. Aim 3 will investigate the potential of personalized therapies for patients with ME2 loss by utilizing spontaneous models and patient-derived xenografts and evaluate biomarkers and molecular regulators of their efficacy. Collectively, the proposed studies employ an innovative and integrative approach to elucidate the molecular basis of ME2 loss-mediated tumor progression and may uncover additional personalized therapies and biomarkers of therapeutic efficacies for the treatment of aggressive pancreatic cancer.