The tumor-suppressive role of ALK4/ACVR1B in pancreatic tumorigenesis

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Pancreatic cancer is the fifth leading cause of cancer death in this country and it is almost uniformly fatal. The poor prognosis of pancreatic cancer patients can be attributed to the lack of early detections and effective treatments. Genetic engineered mice have been effective tools for cancer modeling and pathway studies. A genetic engineered mouse model that simulate a cancer type can be utilized for tumor marker discovery and contribute to the development of early detections. It can also further our understanding of a particular signaling pathway that is important for pancreatic tumorigenesis and lead to the development of designer drugs that are pathway-specific. Here we propose to study activin signaling pathway in genetic engineered mice, because we have previously shown that activin signaling pathway is important for human pancreatic tumorigenesis and this pathway and its funiton in tumor-suppression have not been investigated in vivo. The TGFa receptor superfamily (TGFa, activin, and BMP receptors) and their mediators are critical to pancreatic development and tumorigenesis. We have shown previously that activin type I receptor B (ALK4/ACVR1B) is a tumor-suppressor gene that is biallelically inactivated in pancreatic ductal adenocarcinoma. However, its function in pancreatic tumorigenesis is largely unknown. The objective of this proposal is to investigate the tumor-suppressive function of ALK4/ACVR1B in pancreatic tumorigenesis in Alk4 conditional knock-out mouse models because conventional knockout mice at the Alk4 gene locus are embryonic lethal. We will also investigate the intrinsic relationship between Alk4 and Smad4 in tumor suppression in a compound knock-out mouse model. In addition, we would like to explore the possible role of ALK4/ACVR1B in a subset of pancreatic early lesions called intraductal papillary mucinous neoplasm (IPMN), which is distinct from pancreatic ductal adenocarcinoma and its early lesions (pancreatic intraepithelial neoplasia, PanIN). The involvement of ALK4/ACVR1B has not been evaluated in IPMN previously. It is our belief that to understand the biology of the cancer genes that contribute to the development of human pancreatic cancer will help us develop better detection and treatment options. The urgency to detect and treat this deadly disease has prompted the NCI to issue a Progress Review Group report, in which the NCI identifies the development of ?gene-based model systms that faithfully parallel the complex biology of human pancreatic cancer? as one of its research priorities (http://planning.cancer.gov/pdfprgreports/2001pancreatic.pdf). Gene-based animal models that recapitulate human pancreatic cancer will become avaialbe if this proposal is funded. This grant is 100% relevant to pancreatic cancer.