Abstract 4966: MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization in mice

Abstract

Abstract Background & Aims: The signal adapter MyD88, an essential component of TLR signaling, plays an important role in gut-microbiome interactions. However, its contribution to colitis-associated cancer (CAC) is still controversial. We investigated whether MyD88 signaling in myofibroblasts contributes to an environment that promotes CAC development. Methods: C57BL/6J mice (control) and mice with myofibroblasts-specific deletion of MyD88 (Fib-MyD88 KO) were performed azoxymethane (AOM)/dextran sodium sulfate (DSS) model or DSS model. Colon tissue was collected and analyzed for inflammation, cell proliferation and macrophage polarization. Primary normal fibroblasts (NFs) were isolated and measured for mechanisms that induced macrophage polarization. Results: Myofibroblasts MyD88-deficient mice were resistant to AOM/DSS-induced tumorigenesis, as evidence by the decrease in the number and sizes of tumors. MyD88 deficiency in myofibroblasts did not affect the inflammatory response but attenuated intestinal epithelial cell (IEC) proliferation after acute DSS-induced colitis. Furthermore, MyD88 signaling in myofibroblasts increased the secretion of osteopontin (OPN), which promoted macrophage M2 polarization through binding to αvβ3 and CD44, leading to activation of the STAT3 and PPARγ pathways. Conclusions: MyD88 signaling in myofibroblasts crucially contributes to colorectal cancer development and provides a promising therapeutic target for the prevention of colitis-associated carcinogenesis. Citation Format: Jinhua Zhang, Tian Tian, Qi Yuan. MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization in mice [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 4966.