Abstract LB-262: Excessive Wnt activity is insufficient for intestinal tumor growth or regeneration without gp130/Jak2/Stat3 signaling.

Abstract

Abstract The majority of sporadic and familial colorectal cancers (CRC) arise from unregulated, excessive activation of the WNT signaling pathway as a result of impairment mutations in the tumor suppressor gene APC. Meanwhile, controlled activation of WNT signaling is required for intestinal regeneration in response to injury and ensures intestinal homeostasis. Thus far, however, therapeutic targeting of the WNT pathway has proven difficult in human disease. Here, we show genetically that activation of the cytokine-dependent gp130/Jak/Stat3 pathway augments intestinal regeneration in wild-type mice and promotes intestinal tumorigenesis in Apc mutant mice. Conversely, genetic restriction of gp130/Jak/Stat3 signaling suppresses regeneration and inhibits tumor burden despite persistent, excessive WNT activity. Moreover, therapeutic administration of the Jak2-kinase specific inhibitor AZD1480 in mouse models of either sporadic or inherited CRC effectively blocked de novo tumor initiation and progression. Likewise, AZD1480 suppressed the growth of human APC mutant, but not of isogenic APC wild-type, CRC cell lines in vitro and as tumor xenografts. We identify Stat3-dependent Bmi1 induction and the resulting repression of p16 and p21 as the mechanism by which the gp130/Jak/Stat3 pathway modulates the cellular response to excessive WNT signaling. We therefore propose that the gp130/Jak2/Stat3 pathway is rate-limiting selectively for the growth of APC mutant tumors, and that it provides a readily exploitable target for the therapeutic treatment of CRC. Citation Format: Toby Phesse, Michael Buchert, Matthias Ernst. Excessive Wnt activity is insufficient for intestinal tumor growth or regeneration without gp130/Jak2/Stat3 signaling. [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 LB-262. doi:10.1158/1538-7445.AM2013-LB-262