Neuron, 11 May, 2022, DOI：https://doi.org/10.1016/j.neuron.2022.04.024

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

Pingping Zhu, Tiankun Lu, Zhenzhen Chen, Benyu Liu, Dongdong Fan, Chong Li, Jiayi Wu Luyun He, Xiaoxiao Zhu, Ying Du, Yong Tian, Zusen Fan

Abstract

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 colorectal CSCs and engage with 5-HT to initiate Wnt/β-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.

Article link：https://www.sciencedirect.com/science/article/pii/S0896627322003695?via%3Dihub