Abstract 98: A novel mouse model for intestinal serrated polyposis

Abstract

Abstract Serrated polyps have recently been proposed to comprise at least 30% of the origins of human colorectal cancer (CRC). Unlike adenomatous polyps, which are initiated by APC/β-catenin mutations, the genetic and molecular mechanisms underlying the serrated pathway that leads to serrated polyp initiation and progression remain poorly understood. Here we describe a novel genetically modified mouse model of serrated polyposis via conditional activation of SMAD7, an inhibitory SMAD protein, in the intestinal epithelia. We show that SMAD7 activation is sufficient to drive serrated polyp initiation and progression to aggressive adenocarcinoma in both mouse intestine and colon. Mechanistically, we find that SMAD7-induced foci formation in non-transformed intestinal epithelial cells in vitro and serrated polyposis in vivo are Wnt/β-catenin independent. Furthermore, we find that, in addition to its regulation of TGFβ/BMP pathway, SMAD7 interacts with BRAF/MAPK signaling to regulate serrated polyposis. Taken together, our studies implicate for the first time the involvement of SMAD7 in serrated polyposis and reveal a potential novel molecular mechanism underlying the serrated polyp pathway. Citation Format: Jennifer Cotton, He Huang, Mihir Rajurkar, Junhao Mao. A novel mouse model for intestinal serrated polyposis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 98. doi:10.1158/1538-7445.AM2014-98