Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1

Wei Ma; Lu Zhang; Weilong Chen; Zhaoxia Chang; Juchuanli Tu; Yuanyuan Qin; Yuwen Yao; Mengxue Dong; Jiajun Ding; Siqin Li; Fengkai Li; Qiaodan Deng; Yifei Yang; Tingting Feng; Fanrong Zhang; Xiying Shao; Xueyan He; Lixing Zhang; Guohong Hu; Quentin Liu; Yi-Zhou Jiang; Shu Zhu; Zhi Xiao; Dan Su; Tong Liu; Suling Liu

doi:10.1093/procel/pwae005

Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1

Protein Cell. 2024 May 28;15(6):419-440. doi: 10.1093/procel/pwae005.

Authors

Wei Ma¹, Lu Zhang¹, Weilong Chen^{1

2}, Zhaoxia Chang¹, Juchuanli Tu¹, Yuanyuan Qin^{1

2}, Yuwen Yao¹, Mengxue Dong¹, Jiajun Ding^{1

3}, Siqin Li¹, Fengkai Li¹, Qiaodan Deng¹, Yifei Yang⁴, Tingting Feng⁵, Fanrong Zhang⁶, Xiying Shao⁷, Xueyan He¹, Lixing Zhang¹, Guohong Hu⁸, Quentin Liu⁹, Yi-Zhou Jiang¹, Shu Zhu⁴, Zhi Xiao¹⁰, Dan Su⁵, Tong Liu^{11

12}, Suling Liu^{1

13}

Affiliations

¹ Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Cancer Institutes, Department of Oncology, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
² Intelligent Pathology Institute and Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230071, China.
³ Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
⁴ Institute of Immunology, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China.
⁵ Department of Pathology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
⁶ Department of Breast Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
⁷ Department of Breast Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
⁸ Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
⁹ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
¹⁰ Department of Breast Surgery, Xiangya Hospital, Changsha 410008, China.
¹¹ Department of Breast Surgery, Tumor Hospital of Harbin Medical University, Harbin 150081, China.
¹² Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China.
¹³ Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.

Abstract

Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+ breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs.

Keywords: BFT-1; ETBF; NOD1; breast cancer stem cell; chemoresistance; microbiota.

MeSH terms

Animals
Bacterial Toxins / genetics
Bacterial Toxins / metabolism
Bacteroides fragilis* / genetics
Bacteroides fragilis* / metabolism
Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Breast Neoplasms* / microbiology
Breast Neoplasms* / pathology
Cell Line, Tumor
Drug Resistance, Neoplasm*
Female
Humans
Metalloendopeptidases
Mice
Neoplastic Stem Cells* / metabolism
Neoplastic Stem Cells* / pathology
Nod1 Signaling Adaptor Protein* / genetics
Nod1 Signaling Adaptor Protein* / metabolism

Substances

Nod1 Signaling Adaptor Protein
NOD1 protein, human
Bacterial Toxins
Bacteroides fragilis toxin
Metalloendopeptidases

Abstract

MeSH terms

Substances

Grants and funding