Linking epigenetic regulation and TGF-β signaling in pancreatic cancer

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Project Summary/Abstract Pancreatic adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the US by 2020 with an overall five-year survival rate of <9%. Early metastasis is one of the main reasons for poor survival. Recent genome sequencing studies comparing primary tumor and metastases determined that similar mutations are present, but no specific metastasis drivers were identified. Thus, mechanisms responsible for tumor progression—and specifically for metastasis—require more investigation. Epigenomic regulation and epithelial to mesenchymal transition (EMT) are two important mechanisms for tumor progression and metastasis. We have discovered that miR455 links Transforming Growth Factor-β (TGF-β) and EMT signaling to histone modification. miR455 is upregulated by TGF-β, which in turn reduces the expression of KMT2D and KDM6A, two histone modification enzymes. Our data also revealed that increased miR455 or loss of KDM6A expression promoted PDAC cell EMT phenotype, migration, invasion, lymph node metastasis, and poor patient survival. In this proposal, we will define miR455-mediated novel cross talk between the TGF-β signaling and epigenetic modification in PDAC progression and metastasis. Our project will shed light on the poorly- understood epigenetic regulatory mechanisms in PDAC progression and metastasis, which will further contribute to the identification of new diagnostic and prognostic biomarkers and therapeutic targets. The overall goal of this application is to provide me more protected research time, obtain preliminary data and publication in the epigenetic research field, and develop new critical skills for me to become an R01-funded independent investigator in epigenetics and pancreatic cancer biology. The career development plan is based on formal courses, workshops, lectures, conferences, experiential learning and mentored basic science training. This K08 award and additional training is critical to my career development because of the basic science gap during my clinical training, the development of new knowledge and technologies in the field, and my current clinical duties. I have received generous support from my department and will work closely with my primary mentor, Dr. Yali Dou, PhD, an expert in epigenetics, and co-mentors Drs. Mats Ljungman, PhD, a leader in transcriptional regulation and bioinformatics, and Marina Pasca di Magliano, a leader in the pancreatic cancer field and expert in the generation and analysis of genetic mouse models. I have also constructed an advisory committee to further support my development as a successful physician scientist. I will devote at least 75% of my time to basic scientific research. The University of Michigan and Department of Pathology has a distinguished history in the training of independent cancer researchers. Together, the elements of this proposal will provide me with the experience, training, and mentorship needed to become a successful independent physician-scientist in the field of epigenetics and pancreatic cancer.