Abstract 2735: Inactivation of activin signaling pathway accelerates the development of pancreatic intraductal papillary mucinous neoplasms in vivo.
Authors: Qiu Wanglong , Tang Sophia , Lee Sohyae , Turk Andrew T. , Sireci Anthony , Qiu Anne , Hruban Ralph H. , Remotti Helen E. , Su Gloria H. 
Published: August 2014

Abstract
The association of TGF-β pathway with human tumorigenesis has been rigorously demonstrated. However, little is known about activin signaling, part of the TGF-β family, in pancreatic tumorigenesis. We have previously reported sporadic mutations of the Activin receptor type 1B (ACVR1B) in human pancreatic ductal adenocarcinoma (PDAC). To investigate the significance of ACVR1B in pancreatic tumorigenesis, Acvr1bflox/flox; Pdx1-Cre mice were generated and examined. Chronic pancreatitis-like histological changes such as inflammatory cell infiltration, acinar to ductal metaplasia, and fibrosis were observed in Acvr1b mutant alone mice older than 8 months of age. In combination with mutant KrasG12D in the pancreas, Acvr1b deletion accelerated the development of pancreatic intraductal papillary mucious neoplasms (IPMN), but not the pancreatic intraepithelial neoplasias (PanINs). The IPMN progressed to invasive and metastatic cancer was observed in this model. The expressions of Cox-2 and phospho-PDK1 are dramatically increased in preneoplastic and neoplastic lesions, but activated Notch4 expression is exclusively observed in the IPMN lesions by immunohistochemistry, suggesting that Notch4 signaling may play a role in the formation or maintenance of the mucin-rich ductal phenotype in this model. Interestingly, the progression of IPMN to invasive cancer appears to require additional p16 loss in this double mutant mouse model. In human IPMN, loss of p16 expression is associated with increasing grade. Our data provide the first evidence that Acvr1b acts as a tumor-suppressor in vivo and that activin signaling plays a predominant role in the development of pancreatic IPMNs.
Significance: PDAC can arise from PanINs or IPMN. It has been reported previously that disruption of TGF-β signaling promotes the progression of PanIN to
PDAC in the TGFβRII knockout background. In contrast, here we present that activin signaling deficiency favors the development of IPMNs and enhances their progression to PDAC. This phenotype overlaps with those observed in the Smad4 knockout background, suggesting that the involvement of activin signaling in the IPMN to PDAC sequence is Smad4-dependent. Together these data demonstrate that TGF-β superfamily ligands play critical roles in regulating the IPMN-derived versus PanIN-derived carcinogenesis.
Citation Format: Wanglong Qiu, Sophia Tang, Sohyae Lee, Andrew T. Turk, Anthony Sireci, Anne Qiu, Ralph H. Hruban, Helen E. Remotti, Gloria H. Su. Inactivation of activin signaling pathway accelerates the development of pancreatic intraductal papillary mucinous neoplasms in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2735. doi:10.1158/1538-7445.AM2013-2735