Abstract 440: Dual role of epithelial MyD88 inApc-mutant intestinal tumors

Abstract

Abstract Mutational activation of the Wnt/β-catenin signaling plays essential roles in initiating the adenoma-carcinoma sequence for the majority of colorectal cancers (CRCs) as well as in maintaining the transformed phenotypes of progressed CRCs. However, the Wnt/β-catenin signaling itself is not easy to target for therapy. Here we addressed the roles of MyD88, a critical adaptor protein in the interleukin (IL)-1β and Toll-like receptor (TLR) pathways, in intestinal epithelial cells (IECs) during intestinal tumor formation in Apc+/Δ716 mice, a mouse model of familial adenomatous polyposis as well as the early-stage spontaneous colorectal cancer. Conditional knockout of MyD88 in IECs significantly reduced the number of intestinal tumors in Apc+/Δ716 mice. Although suppression of tumor formation in Apc mutant mice by IEC-specific knockout of MyD88 was previously reported by others, our mechanistic studies uncovered the downstream molecular pathways of MyD88 involved in tumor formation. (1) IEC-specific MyD88 loss induced inactivation of the JNK/mTORC1 signaling, a pathway we previously demonstrated to be essential in the growth of Apc+/Δ716 tumors, leading to decreased proliferation of tumor cells in vivo. (2) IEC-specific MyD88 loss reduced the level of NF-κB p65 and attenuated the Wnt/β-catenin signaling, leading to apoptosis of intestinal tumor cells in vivo. (3) Induction of MyD88 deletion in the intestinal tumor-derived organoids, but not in the normal IEC-derived organoids, caused apoptotic cell death and suppressed their growth in vitro. (4) Knockdown of MYD88 in colorectal cancer cell lines harboring mutations in the Wnt/β-catenin signaling reduced their proliferation and induced apoptosis. These results demonstrate a novel mechanism by which epithelial MyD88 contributes to intestinal tumorigenesis, and also suggest synthetic lethality between MyD88 deficiency and mutations in the Wnt/β-catenin signaling in CRCs. Citation Format: Rie Kajino-Sakamoto, Teruaki Fujishita, Makoto Mark Taketo, Masahiro Aoki. Dual role of epithelial MyD88 inApc-mutant intestinal tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 440.