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Fusobacterium nucleatum-driven mitophagy facilitates endosymbiosis in macrophages and promotes esophageal squamous cell carcinoma metastasis

ABSTRACT: The facultative intracellular bacterium Fusobacterium nucleatum (Fn) mediates tumorigenesis and progression in esophageal squamous cell carcinoma (ESCC). The intracellular survival strategy of Fn and whether Fn can spread through cell‒cell contact in intratumoral tissues and, if so, the underlying mechanisms and implications are currently unknown. Here, we observed that Fn accumulates in macrophages from ESCC tumors and paracancerous normal tissues. We further found that Fn-induced macrophage mitophagy through the PINK1-Parkin-independent pathway decreases excessive mitochondrial ROS production to promote survival. Furthermore, Fn drives a biphasic metabolic switch between glycolysis and oxidative phosphorylation in macrophages to support the bioenergetic demands of survival. Notably, Fn is carried and delivered to tumors by macrophages, where it promotes tumor metastasis via the CCL2-CCR2 axis in ESCC. Treatment with a mitochondrial division inhibitor (mdivi-1) reduced the intracellular Fn concentration and inhibited Fn-positive tumor metastasis in mice. These findings indicate that mitophagy inhibitors or mitophagy machinery targeting may serve as efficient therapeutic strategies to treat Fn-positive tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268689 | GEO | 2025/08/01

REPOSITORIES: GEO

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Project description:Background: Esophageal squamous cell carcinoma (ESCC) has become an important global health issue. The M2 polarization of tumor-associated macrophages (TAMs) plays a key role in the occurrence and development of ESCC. It is reported that exosome circRNAs are involved in the regulation of the polarization state of TAMs, but the underlying mechanism remains unclear. In this study, we aim to identify novel exosome circrnas that regulate the progression of ESCC and explore their biological functions and regulatory mechanisms in ESCC. Method: The highly expressed circRNAs in ESCC tissues and plasma were identified by circRNA microarray analysis. Transmission electron microscopy, differential centrifugation and Western blotting were used for the presence of exosome circAP2B, and the uptake of circAP2B1 by macrophages was determined by exosome tracing. The effects of exosome circAP2B1 on tumor proliferation and metastasis were investigated in vitro and in vivo. The role and molecular mechanism of exosome circAP2B1 in enhancing mitochondrial homeostasis of macrophages to induce M2 polarization were investigated by means of flow cytometry analysis, IP, LC-MS/MS, RIP, Pull down, CHIP, CHRIP and dual-luciferase reporter gene. Result: We demonstrated that the upregulation of exosome circAP2B1 expression was positively correlated with lymph node metastasis and poor prognosis in patients with ESCC. Functionally, exosome circAP2B1 promotes the growth and metastasis of ESCC both in vitro and in vivo by inducing TMS-M2 polarization. Mechanism speaking, the tumor-derived exosome circAP2B1 enters macrophages to promote the nuclear translocation of the circAP2B1/ESRRA/KPNA1 ternary complex and mediate the transcriptional regulation of MFN2 to enhance the mitochondrial homeostasis of TAMs. Conclusion: The exosome circAP2B1 derived from ESCC cells induces TMS-M2 polarization and tumor progression by regulating mitochondrial metabolic reprogramming in macrophages. Therefore, circAP2B1 targeting exosome packaging may provide potential diagnostic and therapeutic strategies for ESCC.

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Fusobacterium nucleatum-driven mitophagy facilitates endosymbiosis in macrophages and promotes esophageal squamous cell carcinoma metastasis

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