Fusobacterium nucleatum induces chemoresistance in colorectal cancer by inhibiting pyroptosis via the Hippo pathway

Ni Wang; Lu Zhang; Xiao-Xu Leng; Yi-Le Xie; Zi-Ran Kang; Li-Cong Zhao; Lin-Hong Song; Cheng-Bei Zhou; Jing-Yuan Fang

doi:10.1080/19490976.2024.2333790

Fusobacterium nucleatum induces chemoresistance in colorectal cancer by inhibiting pyroptosis via the Hippo pathway

Gut Microbes. 2024 Jan-Dec;16(1):2333790. doi: 10.1080/19490976.2024.2333790. Epub 2024 Mar 27.

Authors

Ni Wang^{1

2}, Lu Zhang¹, Xiao-Xu Leng¹, Yi-Le Xie¹, Zi-Ran Kang¹, Li-Cong Zhao¹, Lin-Hong Song¹, Cheng-Bei Zhou¹, Jing-Yuan Fang¹

Affiliations

¹ Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Gastroenterology; Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Chemotherapy resistance is one of the main reasons for the poor prognosis of colorectal cancer (CRC). Moreover, dysbiosis of gut bacteria was found to be a specific environmental risk factor. In this study, enrichment of F. nucleatum was elucidated to be significantly associated with CRC recurrence after chemotherapy. Functional experiments showed that F. nucleatum could inhibit pyroptosis induced by chemotherapy drugs, thereby inducing chemoresistance. Furthermore, mechanistic investigation demonstrated that F. nucleatum could regulate the Hippo pathway and promote the expression of BCL2, thereby inhibiting the Caspase-3/GSDME pyroptosis-related pathway induced by chemotherapy drugs and mediating CRC cell chemoresistance. Taken together, these results validated the significant roles of F. nucleatum in CRC chemoresistance, which provided an innovative theoretical basis for the clinical diagnosis and therapy of CRC.

Keywords: Fusobacterium nucleatum; GSDME; YAP; chemoresistance; colorectal cancer; pyroptosis.

Publication types

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

MeSH terms

Colorectal Neoplasms* / microbiology
Drug Resistance, Neoplasm
Fusobacterium nucleatum / physiology
Gastrointestinal Microbiome*
Hippo Signaling Pathway
Humans
Neoplasm Recurrence, Local
Pyroptosis

Grants and funding

We thank all patients and individuals for their participation in our study. This project was supported in part by grants from the National Key R&D Program of China (2020YFA0509200), National Natural Science Foundation of China (81830081, 31970718, 32100138, 82203224), Shanghai Municipal Health Commission, Collaborative Innovation Cluster Project (2019CXJQ02), Chenguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (22CGA17), China Postdoctoral Science Foundation (2022M712124), Shanghai “Rising Stars of Medical Talents” Youth Development Specialist Program (2023-62), Clinical Research Plan of SHDC (SHDC2020CR1034B), Shanghai Sailing Program (21YF1425600) and Innovative research team of high-level local universities in Shanghai.