Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma

Yang Liu; Yoshifumi Baba; Takatsugu Ishimoto; Hiroyasu Tsutsuki; Tianli Zhang; Daichi Nomoto; Kazuo Okadome; Kensuke Yamamura; Kazuto Harada; Kojiro Eto; Yukiharu Hiyoshi; Masaaki Iwatsuki; Yohei Nagai; Shiro Iwagami; Yuji Miyamoto; Naoya Yoshida; Yoshihiro Komohara; Masaki Ohmuraya; Xiaoming Wang; Jaffer A. Ajani; Tomohiro Sawa; Hideo Baba

doi:10.1038/s41416-020-01198-5

Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma

Yang Liu, Yoshifumi Baba, Takatsugu Ishimoto, Hiroyasu Tsutsuki, Tianli Zhang, Daichi Nomoto, Kazuo Okadome, Kensuke Yamamura, Kazuto Harada, Kojiro Eto, Yukiharu Hiyoshi, Masaaki Iwatsuki, Yohei Nagai, Shiro Iwagami, Yuji Miyamoto, Naoya Yoshida, Yoshihiro Komohara, Masaki Ohmuraya, Xiaoming Wang, Jaffer A. AjaniTomohiro Sawa, Hideo Baba

GI Medical Oncology

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

Abstract

Background: Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic strategies for oesophageal cancer patients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC). Methods: We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance. Results: ESCC patients with F. nucleatum infection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatum infection and ATG7 expression in 284 ESCC specimens. Conclusions: F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.

Original language	English (US)
Pages (from-to)	963-974
Number of pages	12
Journal	British journal of cancer
Volume	124
Issue number	5
DOIs	https://doi.org/10.1038/s41416-020-01198-5
State	Published - Mar 2 2021

ASJC Scopus subject areas

Oncology
Cancer Research

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Liu, Y., Baba, Y., Ishimoto, T., Tsutsuki, H., Zhang, T., Nomoto, D., Okadome, K., Yamamura, K., Harada, K., Eto, K., Hiyoshi, Y., Iwatsuki, M., Nagai, Y., Iwagami, S., Miyamoto, Y., Yoshida, N., Komohara, Y., Ohmuraya, M., Wang, X., ... Baba, H. (2021). Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma. British journal of cancer, 124(5), 963-974. https://doi.org/10.1038/s41416-020-01198-5

Liu, Y, Baba, Y, Ishimoto, T, Tsutsuki, H, Zhang, T, Nomoto, D, Okadome, K, Yamamura, K, Harada, K, Eto, K, Hiyoshi, Y, Iwatsuki, M, Nagai, Y, Iwagami, S, Miyamoto, Y, Yoshida, N, Komohara, Y, Ohmuraya, M, Wang, X, Ajani, JA, Sawa, T & Baba, H 2021, 'Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma', British journal of cancer, vol. 124, no. 5, pp. 963-974. https://doi.org/10.1038/s41416-020-01198-5

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title = "Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma",

abstract = "Background: Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic strategies for oesophageal cancer patients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC). Methods: We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance. Results: ESCC patients with F. nucleatum infection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatum infection and ATG7 expression in 284 ESCC specimens. Conclusions: F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.",

author = "Yang Liu and Yoshifumi Baba and Takatsugu Ishimoto and Hiroyasu Tsutsuki and Tianli Zhang and Daichi Nomoto and Kazuo Okadome and Kensuke Yamamura and Kazuto Harada and Kojiro Eto and Yukiharu Hiyoshi and Masaaki Iwatsuki and Yohei Nagai and Shiro Iwagami and Yuji Miyamoto and Naoya Yoshida and Yoshihiro Komohara and Masaki Ohmuraya and Xiaoming Wang and Ajani, {Jaffer A.} and Tomohiro Sawa and Hideo Baba",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Cancer Research UK.",

year = "2021",

month = mar,

day = "2",

doi = "10.1038/s41416-020-01198-5",

language = "English (US)",

volume = "124",

pages = "963--974",

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TY - JOUR

T1 - Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma

AU - Liu, Yang

AU - Baba, Yoshifumi

AU - Ishimoto, Takatsugu

AU - Tsutsuki, Hiroyasu

AU - Zhang, Tianli

AU - Nomoto, Daichi

AU - Okadome, Kazuo

AU - Yamamura, Kensuke

AU - Harada, Kazuto

AU - Eto, Kojiro

AU - Hiyoshi, Yukiharu

AU - Iwatsuki, Masaaki

AU - Nagai, Yohei

AU - Iwagami, Shiro

AU - Miyamoto, Yuji

AU - Yoshida, Naoya

AU - Komohara, Yoshihiro

AU - Ohmuraya, Masaki

AU - Wang, Xiaoming

AU - Ajani, Jaffer A.

AU - Sawa, Tomohiro

AU - Baba, Hideo

PY - 2021/3/2

Y1 - 2021/3/2

N2 - Background: Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic strategies for oesophageal cancer patients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC). Methods: We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance. Results: ESCC patients with F. nucleatum infection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatum infection and ATG7 expression in 284 ESCC specimens. Conclusions: F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.

AB - Background: Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic strategies for oesophageal cancer patients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC). Methods: We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance. Results: ESCC patients with F. nucleatum infection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatum infection and ATG7 expression in 284 ESCC specimens. Conclusions: F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.

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DO - 10.1038/s41416-020-01198-5

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AN - SCOPUS:85097272613

SN - 0007-0920

VL - 124

SP - 963

EP - 974

JO - British journal of cancer

JF - British journal of cancer

IS - 5

ER -

Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma

Abstract

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