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

• Published in: British journal of cancer Vol. 124; no. 5; pp. 963 - 974
• Main Authors: Liu, Yang, Baba, Yoshifumi, Ishimoto, Takatsugu, Tsutsuki, Hiroyasu, Zhang, Tianli, Nomoto, Daichi, Okadome, Kazuo, Yamamura, Kensuke, Harada, Kazuto, Eto, Kojiro, Hiyoshi, Yukiharu, Iwatsuki, Masaaki, Nagai, Yohei, Iwagami, Shiro, Miyamoto, Yuji, Yoshida, Naoya, Komohara, Yoshihiro, Ohmuraya, Masaki, Wang, Xiaoming, Ajani, Jaffer A., Sawa, Tomohiro, Baba, Hideo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-03-2021; Nature Publishing Group
• Subjects: 631/67/1504/1477; 631/67/1857; Autophagy; Biomedical and Life Sciences; Biomedicine; Biopsy; Cancer Research; Cell culture; Chemoresistance; Chemotherapy; Confocal microscopy; Drug Resistance; Epidemiology; Esophageal cancer; Esophagus; Fusobacterium nucleatum; Metastases; Microscopy; Molecular Medicine; Oncology; Phagocytosis; Squamous cell carcinoma; Transmission electron microscopy; Tumorigenesis
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-01198-5

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.