Although cancer-associated fibroblasts display marked transcriptional heterogeneity, how they dynamically reprogram and contribute to tumor progression remains unclear. By integrating single-cell and spatial transcriptomics with in vitro co-culture, we constructed a spatiotemporal atlas of extracellular matrix-constituting (ECM) fibroblasts in gastric cancer. We identify a directed trajectory in which homeostatic (ECMh) fibroblasts transition through an inflammatory intermediate (ECMi) toward tissue-remodeling (ECMr) fibroblasts, accompanied by ECMr-specific GLIS2 regulon activation and spatially oriented toward the tumor invasion front. ECMr fibroblasts activate a wound healing-like program in adjacent malignant cells, comprising de novo laminin-332 production, hemidesmosome assembly, and a wound healing-type protease pattern, while suppressing proliferation and epithelial-mesenchymal transition (EMT). Stromal GLIS2 regulon activity independently predicts peritoneal metastasis-free survival in gastric and colorectal cohorts, and this stromal architecture is recapitulated at peritoneal metastases. Stromal reprogramming, rather than tumor-intrinsic EMT, emerges as a hemidesmosome-linked paradigm of peritoneal dissemination.
Lee, S., Cho, S., Han, D.-S., Kim, J., Hur, H., Kim, H. H., Cheong, J.-H., Kim, T.-M.
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