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

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

doi:10.1038/s41416-020-01198-5

Abstract

BackgroundFusobacterium 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).MethodsWe 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.ResultsESCC 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.ConclusionsF. 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.

Highlights

Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis
We examined the relationship between F. nucleatum and poor chemotherapy response in 120 resected ESCC specimens and 30 pre-treatment biopsy specimens
The analyses revealed that patients with a higher burden of F. nucleatum had significantly fewer responders (i.e. patients with complete metabolic response (CMR) or partial metabolic response (PMR); 37.0% (10/27) vs. 88.2% (60/68) in the low F. nucleatum group; P < 0.001; Fig. 1c)

Summary

Introduction

Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. 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. Squamous cell carcinoma is the most common pathological type of oesophageal cancer in the world, especially in Asia, parts of Africa, and Europe.[1,2] The prognosis of oesophageal cancer is poor and only about 19% of the patients survive for 5 years.[3] Based on multiple clinical studies, preoperative chemotherapy or chemoradiation followed by esophagectomy has become the preferred multimodal treatment for patients with resectable oesophageal cancer.[4,5] Docetaxel, cisplatin (CDDP), and 5fluorouracil (FU) are the key chemotherapeutic agents used to treat oesophageal squamous cell carcinoma (ESCC).[6,7] Identification of novel therapeutic targets in ESCC could potentially improve the risk-adapted treatment strategies and help develop rational clinical trials, in which patients may be selected based on biomarkers

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