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

doi:10.1016/j.neuron.2022.04.024

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

Neuron. 2022 Jul 20;110(14):2268-2282.e4. doi: 10.1016/j.neuron.2022.04.024. Epub 2022 May 12.

Authors

Pingping Zhu¹, Tiankun Lu², Zhenzhen Chen³, Benyu Liu⁴, Dongdong Fan⁵, Chong Li⁶, Jiayi Wu⁷, Luyun He⁸, Xiaoxiao Zhu⁵, Ying Du⁹, Yong Tian¹⁰, Zusen Fan¹¹

Affiliations

¹ CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan 450052, China. Electronic address: zhup@zzu.edu.cn.
² CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
⁴ CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Research Center of Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
⁵ CAS Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁶ Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Zhongke Jianlan (Beijing) Institute of Medicine, Beijing 101407, China.
⁷ CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
⁸ CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan 450052, China; Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
⁹ CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
¹⁰ University of Chinese Academy of Sciences, Beijing 100049, China; CAS Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: ytian@ibp.ac.cn.
¹¹ CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: fanz@moon.ibp.ac.cn.

PMID: 35550066
DOI: 10.1016/j.neuron.2022.04.024

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.

Keywords: 5-HT; colorectal cancer stem cell; enteric serotonergic neuron; gut microbiota; self-renewal.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis
Cell Line, Tumor
Cell Self Renewal*
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / metabolism
Colorectal Neoplasms* / pathology
Mice
Serotonergic Neurons / metabolism
Serotonin
Wnt Signaling Pathway

Substances

Serotonin