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bioRxiv · 10.64898/2026.05.21.726806

Developmental plasticity of cancer-associated fibroblasts contributes to the malignant progression of gastric cancers

Lee, S.·Cho, S.·Han, D.-S.·Kim, J.·Hur, H.·Kim, H. H.·Cheong, J.-H.·Kim, T.-M.
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Abstract

Cancer-associated fibroblasts are transcriptionally heterogeneous, yet how their reprogramming shapes gastric cancer progression remains unclear. Integrating single-cell and spatial transcriptomics, patient-derived fibroblast co-culture, and clinical cohorts, we identified a spatially organized continuum of extracellular matrix-producing fibroblasts. An inferred trajectory connected homeostatic ECMh through inflammatory-chemoattractive ECMi to tissue-remodeling ECMr, with increasing GLIS2 regulon activity and ECMr enrichment near the tumor-stroma interface. ECMr co-culture induced a non-EMT epithelial program characterized by coordinated laminin-332 subunit expression, hemidesmosome-associated genes, a matrix-remodeling protease profile, and reduced proliferative activity. Longitudinal imaging showed progressive cancer-cell elongation and positional displacement over the fibroblast layer. ECMr-associated GLIS2 regulon activity in resected primary tumors was associated with shorter peritoneal metastasis-free survival across two gastric cancer cohorts, with a similar association in colorectal cancer. A peritoneal metastasis recapitulated the corresponding stromal and epithelial organization. Together, these findings define an ECMr-centered stromal-epithelial wound-repair circuit linked to subsequent peritoneal dissemination.

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Lee, S., Cho, S., Han, D.-S., Kim, J., Hur, H., Kim, H. H., Cheong, J.-H., Kim, T.-M.. 2026-05-22. Developmental plasticity of cancer-associated fibroblasts contributes to the malignant progression of gastric cancers. https://doi.org/10.64898/2026.05.21.726806

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