Background Gastric microbiota dysbiosis is closely linked to chronic inflammation and carcinogenesis. Fusobacterium nucleatum (Fn), an opportunistic gastrointestinal pathogen, is implicated in perturbing the immune system and form an inflammatory microenvironment that fuels the occurrence and progression of gastric cancer (GC). However, the underlying mechanisms remain elusive. We aimd to investigate the impacts of Fn on GC cells and the crosstalk between GC cells and mast cells (MCs). Methods Fn abundance and MC infiltration were assessed in clinical GC tissues. Cell-based functional experiments, including wound healing, transwell, and ELISA, were performed using conditioned medium-based co-culture systems to explore how Fn influenced GC cell migration and the crosstalk with MC. A murine lung metastasis model was employed to evaluate Fn-driven metastasis and the effects of metronidazole and Reparixin. Results We showed that Fn and MCs were enriched and positively correlated in clinical GC tissues compared to paracancerous tissues. Fn and MCs exhibited tumor-promoting properties by facilitating GC cell migration. Besides, Fn and GC cells can recruit MCs and facilitate its activation. This crosstalk between GC cells and MCs was further enhanced by Fn, thereby amplifying this positive feedback loop between them. The production of CXCL8 in response to Fn stimulation was a significant mediator. Suppression of CXCL8 in GC cells weakened Fn’s promoting effects on GC cell migration, MC recruitment and activation. Similarly, knocking down CXCL8 in MCs reversed the Fn-induced feedback effect of MCs on the highly invasive phenotype of GC cells. Mechanistically, the exoprotein Gbp of Fn activated CypA-NF-κB pathway in both GC cells and MCs, leading to the upregulation of CXCL8 expression. In addition, the in vivo assays substantiated Fn’s ability to enhance tumor progression by facilitating cell migration, upregulating CXCL8 expression, and inducing MC infiltration and activation. However, these effects were reversed by metronidazole, a highly Fn-susceptible antibiotic, and Reparixin. Conclusions In summary, this study suggests that Fn contributes to GC progression by promoting tumor cell migration, MCs recruitment and activation. Simultaneously, the enhanced CXCL8-mediated crosstalk between GC cells and MCs plays a vital role in the pro-cancer effect of Fn.

Fusobacterium nucleatum drives gastric cancer metastasis via Gbp-CypA-NF-κB-mediated CXCL8 crosstalk between tumor cells and mast cells

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2025年11月28日

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Xinyi Yang,
Tingting Ning,
Wanru Zhang,
Songyuan Hou,
Jiayi Su,
Wenkun Li,
Jing Wu

摘要

Background

Gastric microbiota dysbiosis is closely linked to chronic inflammation and carcinogenesis. Fusobacterium nucleatum (Fn), an opportunistic gastrointestinal pathogen, is implicated in perturbing the immune system and form an inflammatory microenvironment that fuels the occurrence and progression of gastric cancer (GC). However, the underlying mechanisms remain elusive. We aimd to investigate the impacts of Fn on GC cells and the crosstalk between GC cells and mast cells (MCs).

Methods

Fn abundance and MC infiltration were assessed in clinical GC tissues. Cell-based functional experiments, including wound healing, transwell, and ELISA, were performed using conditioned medium-based co-culture systems to explore how Fn influenced GC cell migration and the crosstalk with MC. A murine lung metastasis model was employed to evaluate Fn-driven metastasis and the effects of metronidazole and Reparixin.

Results

We showed that Fn and MCs were enriched and positively correlated in clinical GC tissues compared to paracancerous tissues. Fn and MCs exhibited tumor-promoting properties by facilitating GC cell migration. Besides, Fn and GC cells can recruit MCs and facilitate its activation. This crosstalk between GC cells and MCs was further enhanced by Fn, thereby amplifying this positive feedback loop between them. The production of CXCL8 in response to Fn stimulation was a significant mediator. Suppression of CXCL8 in GC cells weakened Fn’s promoting effects on GC cell migration, MC recruitment and activation. Similarly, knocking down CXCL8 in MCs reversed the Fn-induced feedback effect of MCs on the highly invasive phenotype of GC cells. Mechanistically, the exoprotein Gbp of Fn activated CypA-NF-κB pathway in both GC cells and MCs, leading to the upregulation of CXCL8 expression. In addition, the in vivo assays substantiated Fn’s ability to enhance tumor progression by facilitating cell migration, upregulating CXCL8 expression, and inducing MC infiltration and activation. However, these effects were reversed by metronidazole, a highly Fn-susceptible antibiotic, and Reparixin.

Conclusions

In summary, this study suggests that Fn contributes to GC progression by promoting tumor cell migration, MCs recruitment and activation. Simultaneously, the enhanced CXCL8-mediated crosstalk between GC cells and MCs plays a vital role in the pro-cancer effect of Fn.