Neuro-associated SEMA3C+ tumour cells promote gastric cancer peritoneal metastasis via EBF2-FGF7-FGFR2-mediated tumour-endothelial crosstalk.

BACKGROUND

Recent studies have established that the nervous system is not merely a bystander in tumour progression but can actively remodel the tumour microenvironment through the neuro-tumour axis, thereby promoting tumour invasion, metastasis and survival. Semaphorin 3C (SEMA3C) has been reported to regulate tumour migration, angiogenesis and immune suppression, highlighting its potential role in tumour progression. Although the neuro-tumour axis has been identified in multiple cancer types, its role and underlying mechanisms in gastric cancer peritoneal metastasis (GCPM) remain unclear.

METHODS

We performed single-nucleus RNA sequencing (snRNA-seq) of GCPM tissues to profile tumour cell heterogeneity and identify tumour cell populations associated with neural-related signalling. Candidate tumour-microenvironmental interactions were further investigated using patient-derived organoids and co-culture models, and the identified signalling axis was validated using corresponding in vivo models.

RESULTS

SnRNA-seq identified a distinct subpopulation of poorly differentiated tumour cells with pronounced stem-like properties and high SEMA3C expression. This subpopulation was associated with neural-related features and interacted with tumour-associated endothelial cells, thereby contributing to remodelling of the metastatic microenvironment. Furthermore, these cells enhanced tumour-endothelial communication by activating the fibroblast growth factor receptor-associated signalling pathway. The transcription factor early B-cell factor 2 (EBF2) regulates the expression of FGF7 within this subpopulation, thereby strengthening FGF7-FGFR2 signalling and promoting tumour progression. Functional validation further demonstrated that SEMA3C depletion impaired organoid growth and tumour-endothelial interactions, whereas disruption of the SEMA3C-EBF2-FGF7-FGFR2 signalling axis attenuated tumour growth and peritoneal tumour burden in vivo. Additional experimental validation supported the potential involvement of neural-related signalling in the SEMA3C-associated tumour cell state.

CONCLUSIONS

Our findings identify a SEMA3C+ tumour cell subpopulation associated with neural-related signalling and suggest that SEMA3C promotes tumour-endothelial interactions through the EBF2-FGF7-FGFR2 signalling axis, providing a potential mechanistic link between neural regulation and microenvironmental remodelling in peritoneal metastasis of gastric cancer.