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Bifidobacterium adolescentis orchestrates CD143+ cancer-associated fibroblasts to suppress colorectal tumorigenesis by Wnt signaling-regulated GAS1.

Authors
  • Chen, Shujie1, 2, 3, 4
  • Fan, Lina2, 5
  • Lin, Yifeng2, 5
  • Qi, Yadong1, 2
  • Xu, Chaochao2, 5
  • Ge, Qiwei2, 5
  • Zhang, Ying2, 5
  • Wang, Qiwen1, 2
  • Jia, Dingjiacheng2, 5
  • Wang, Lan1, 2
  • Si, Jianmin1, 2, 3, 4
  • Wang, Liangjing2, 3, 4, 5
  • 1 Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P. R. China. , (China)
  • 2 Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, P. R. China. , (China)
  • 3 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, P. R. China. , (China)
  • 4 Research Center of Prevention and Treatment of Senescent Disease, School of Medicine Zhejiang University, Hangzhou, Zhejiang, P. R. China. , (China)
  • 5 Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China. , (China)
Type
Published Article
Journal
Cancer communications (London, England)
Publication Date
Sep 01, 2023
Volume
43
Issue
9
Pages
1027–1047
Identifiers
DOI: 10.1002/cac2.12469
PMID: 37533188
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The interplay between gut microbiota and tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC) is not well explored. Here, we elucidated the functional role of Bifidobacterium adolescentis (B.a) on CRC and investigated its possible mechanism on the manipulation of cancer-associated fibroblasts (CAFs) in CRC. Different CRC animal models and various cell line models were established to explore the function of B.a on CRC. The single-cell RNA sequencing (scRNA-seq) or flow cytometry was used to detect the cell subsets in the TME of CRC. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), or immunofluorescence staining were performed to examine the activation of Wnt signaling and growth arrest specific 1 (GAS1) on CD143+ CAFs. Chromatin immunoprecipitation quantitative real-time PCR (CHIP-qPCR) was performed to investigate the regulation of transcription factor 4 (TCF4) on GAS1. Multi-immunofluorescence assay examined the expression level of CD143 and GAS1 on tissue microarray. We found that B.a abundance was significantly reduced in CRC patients from two independent cohorts and the bacteria database of GMrepo. Supplementation with B.a suppressed ApcMin/+ spontaneous or AOM/DSS-induced tumorigenesis in mice. scRNA-seq revealed that B.a facilitated a subset of CD143+ CAFs by inhibiting the infiltration of Th2 cells, while promoting the TNF-alpha+ B cells in TME. CD143+ CAFs highly expressed GAS1 and exhibited tumor suppressive effect. Mechanistically, GAS1 was activated by the Wnt/β-catenin signaling in CD143+ CAFs. B.a abundance was correlated with the expression level of CD143 and GAS1. The level of CD143+ CAFs predicted the better survival outcome in CRC patients. These results highlighted that B.a induced a new subset of CD143+ CAFs by Wnt signaling-regulated GAS1 to suppress tumorigenesis and provided a novel therapeutic target for probiotic-based modulation of TME in CRC. © 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.

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