Abstract B83: Loss of the Hippo pathway effector Yap disrupts pancreatic morphogenesis and exacerbates exocrine pancreatitis.

Abstract

Background: The Hippo signaling pathway regulates organ size by restricting the activity of the transcriptional co-activator yes-associated protein (YAP), an oncogene implicated in pancreatic cancer. However, the role of YAP in mammalian pancreatic development and homeostasis is not well understood. Methods: Yap was conditionally ablated in the murine pancreas, either during development, using Pdx1-Cre as a “driver” or in the post-natal exocrine pancreas, using tamoxifen-inducible elastase (Ela)-Cre-ERT2 mice. Exocrine pancreatitis was induced by intraperitoneal caerulein administration. Results: Pdx1-Cre;Yapflox/flox mice demonstrated perinatal lethality (29/33 mice), secondary to a malformed pancreas, underscoring the importance of an intact Yap effector for pancreatic development. In wild-type mice, caerulein pancreatitis was associated with nuclear translocation of Yap protein, and upregulation of its bona fide transcriptional targets, survivin, and connective tissue growth factor (CTGF). Caerulein administration in tamoxifen-induced Ela-Cre-ERT2;Yapflox/flox mice resulted in markedly severe (necrotizing) pancreatitis, including the onset of mortality, compared to littermates with retained pancreatic Yap expression. Transcriptional profiling confirmed the failure to induce multiple anti-apoptotic molecules, including survivin, in the absence of Yap protein, which was accompanied by an increase in acinar cell apoptosis. However, neither exocrine regeneration itself, nor the upregulation of canonical signaling pathways implicated in regeneration (Notch and Hedgehog), was significantly abrogated in the absence of Yap. Conclusions: An intact Hippo pathway is essential for pancreatic morphogenesis. In the mature pancreas, absence of Yap profoundly exacerbates exocrine pancreatitis, with subsequent tissue regeneration remaining largely unaffected. Systemic therapeutics directed at negating YAP function in cancer cells need to be cognizant of the requirement for sustained YAP signaling in embryonic and mature tissues. Citation Format: Sonal Gupta, Anirban Maitra, Ji-Kon Ryu, Nailing Zhang, Seungmin Bang, Meritxell Rovira, Hanno Matthaei, Seung-Mo Hong, Steven D. Leach, Duojia Pan. Loss of the Hippo pathway effector Yap disrupts pancreatic morphogenesis and exacerbates exocrine pancreatitis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B83.