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

Summary MyD88, an adaptor molecule downstream of innate pathways, plays a significant tumor-promoting role in sporadic intestinal carcinogenesis of the Apcmin/+ model, which carries a mutation in the Apc gene. Here, we show that deletion of MyD88 in intestinal mesenchymal cells (IMCs) significantly reduces tumorigenesis in this model. 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 interleukin-1 receptor (IL-1R), 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 could be mediated through downstream signals involving growth factors and inflammatory and extracellular matrix (ECM)-regulating genes, also found in human cancer-associated fibroblasts (CAFs). Our results provide direct evidence that during tumorigenesis, IMCs and CAFs are activated by innate TLR4/MyD88-mediated signals and promote carcinogenesis in the intestine.
Graphical Abstract
Highlights • Deletion of MyD88 or TLR4 in IMCs and/or CAFs leads to reduced intestinal tumorigenesis • The phenotype of the IMC-specific MyD88 mice is similar to the complete knockouts • MyD88−/− IMCs show a reduced pro-tumorigenic and/or inflammatory gene expression profile • Human CAFs show upregulation of a similar MyD88-specific gene expression signature
Koliaraki et al. show that MyD88 in mesenchymal cells is responsible for its tumor-promoting role in the Apcmin/+ model. They further show that this is a TLR4-mediated mechanism that leads to the production of pro-tumorigenic molecules, also identified in human CAFs.