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.

结直肠癌干细胞 (CSC) 有助于结直肠肿瘤的发生和转移。结直肠癌干细胞位于专门的生态位内，具有自我更新和分化能力。然而，CSC 的利基法规仍不清楚。在这里，我们表明肠神经细胞是 CSC 自我更新和结直肠肿瘤发生所必需的。肠 5-羟色胺能神经元产生 5-羟色胺 (5-HT) 作为 CSC 自我更新的调节剂。5-HT 受体 HTR1B/1D/1F 在结直肠 CSC 中高度表达，并与 5-HT 结合以启动 Wnt/β-catenin 信号传导。从机制上讲，富含结直肠癌 (CRC) 的微生物群代谢物异戊酸可抑制 NuRD 复合物在Tph2上的富集启动子启动 Tph2 表达，导致 5-HT 产生。5-HT 信号与 CRC 严重程度相关。阻断小鼠体内的 5-HT 信号不仅可以抑制结直肠 CSC 的自我更新，而且还显示出对 CRC 肿瘤的治疗效果。我们的研究结果揭示了肠神经元和肿瘤细胞之间的串扰，作为 CSC 调节的附加层。