Innate Sensing by Mesenchymal TLR4/MyD88 Signals Promotes Spontaneous Intestinal Tumorigenesis

MyD88, an adaptor molecule downstream of innate pathways, plays a significant tumor-promoting role in sporadic intestinal carcinogenesis, which is dependent on its function in the stroma. Here, we show that deletion of MyD88 in intestinal mesenchymal cells (IMCs) significantly reduces Apc-mediated intestinal tumorigenesis. This phenotype is associated with decreased epithelial cell proliferation, altered inflammatory and tumorigenic immune cell infiltration, and modified gene expression similar to complete MyD88 knockout mice. Genetic deletion of TLR4, but not IL1R, in IMCs led to altered molecular profiles and reduction of intestinal tumors similar to the MyD88 deficiency. Ex vivo analysis in IMCs indicated that these effects are mediated through downstream signals involving growth factors, inflammatory and ECM-regulating genes, also found in human cancer-associated fibroblasts (CAFs). Our results provide the first direct evidence that during tumorigenesis, IMCs and CAFs are activated by innate TLR4/MyD88-mediated signals and respond to promote carcinogenesis in the intestine.