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

Columbia University Health Sciences, New York NY

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Abstract

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