Neuro‐associated SEMA3C+ tumour cells promote gastric cancer peritoneal metastasis via EBF2–FGF7–FGFR2‐mediated tumour–endothelial crosstalk
- 1The First Affiliated Hospital of Soochow University
Abstract
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.
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BibTeX
@article{zhou2026neuroassociated,
title = {{Neuro‐associated SEMA3C+ tumour cells promote gastric cancer peritoneal metastasis via EBF2–FGF7–FGFR2‐mediated tumour–endothelial crosstalk}},
author = {Yajing Zhou and Chao Dong and Weikang Li and Minghao Sun and Qingyu Xie and Lixing Gu and Pengbo Wang and Chengxiang Xu and Tianzhan Gao and Caixin Zhu and Kaipeng Duan and Jin Zhou and Dongbao Li},
journal = {Clinical and translational medicine},
year = {2026},
month = oct,
doi = {10.1002/ctm2.70861},
url = {https://europepmc.org/article/PMC/PMC13671878},
note = {CC BY},
}
RIS
TY - JOUR
TI - Neuro‐associated SEMA3C+ tumour cells promote gastric cancer peritoneal metastasis via EBF2–FGF7–FGFR2‐mediated tumour–endothelial crosstalk
AU - Yajing Zhou
AU - Chao Dong
AU - Weikang Li
AU - Minghao Sun
AU - Qingyu Xie
AU - Lixing Gu
AU - Pengbo Wang
AU - Chengxiang Xu
AU - Tianzhan Gao
AU - Caixin Zhu
AU - Kaipeng Duan
AU - Jin Zhou
AU - Dongbao Li
PY - 2026
DA - 2026/10/01
JO - Clinical and translational medicine
DO - 10.1002/ctm2.70861
UR - https://europepmc.org/article/PMC/PMC13671878
AB - 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.
SN - 2001-1326
ER -