5-hydroxytryptamine produced by enteric serotonergic neurons initiates colorectal cancer stem cell self-renewal and tumorigenesis

Colorectal cancer stem cells (CSCs) contribute to colorectal tumorigenesis and metastasis. Colorectal CSCs reside within specialized niches and harbor self-renewal and differentiation capacities. However, the niche regulations of CSCs remain unclear. Here, we show that intestinal nerve cells are required for CSC self -renewal and colorectal tumorigenesis. Enteric serotonergic neurons produce 5-hydroxytryptamine (5-HT) to function as a modulator of CSC self-renewal. 5-HT receptors HTR1B/1D/1F are highly expressed in colo-rectal CSCs and engage with 5-HT to initiate Wnt/b-catenin signaling. Mechanistically, colorectal cancer (CRC)-enriched microbiota metabolite isovalerate suppresses the enrichment of the NuRD complex onto Tph2 promoter to initiate Tph2 expression, leading to 5-HT production. 5-HT signaling is correlated with CRC severity. Blocking 5-HT signaling in mice not only inhibits the self-renewal of colorectal CSCs but also displays therapeutic efficacy against CRC tumors. Our findings reveal a cross talk between intestinal neurons and tumor cells that serves as an additional layer for CSC regulation.

Automated summary

This study reveals the importance of intestinal nerve cells in the self-renewal of colorectal cancer stem cells (CSCs) and the development of colorectal tumors. Serotonergic neurons in the enteric system produce serotonin (5-HT) as a regulator of CSC self-renewal. 5-HT interacts with HTR1B/1D/1F receptors to activate Wnt/β-catenin signaling in colorectal CSCs. Additionally, a metabolite derived from the colorectal cancer-enriched microbiota, isovalerate, suppresses the enrichment of the NuRD complex on the Tph2 promoter, leading to the expression of Tph2 and subsequent 5-HT production. 5-HT signaling is correlated with the severity of colorectal cancer.