Formation of the pre-metastatic niche by COL9A1 + cancer-associated fibroblasts via SDC4 engagement promotes multi-organ metastasis in gastric cancer.

BACKGROUND

Metastatic dissemination represents the primary cause of mortality in gastric cancer (GC), with multi-organ involvement posing a formidable therapeutic challenge. While organ-specific adaptations are well-studied, the conserved cellular programs that confer metastatic competence within primary tumors before dissemination remain poorly defined.

METHODS

We performed integrated single-cell and spatial transcriptomic profiling on paired primary GC tumors and multi-organ metastases. Computational trajectory inference, regulon analysis, and cell-cell communication networks were employed to delineate metastatic evolution. Functional validation was conducted through in vitro models, including co-culture assays and genetic perturbation.

RESULTS

We identified a conserved intra-tumoral trajectory from metastasis-initiating cells (MICs) to metastasis-like cells (MLCs) within primary tumors, which transcriptionally converged with cells from anatomically diverse metastases. This progression was orchestrated by an ETS2-centered regulatory network, whose declining activity governed pre-adaptive remodeling. We further resolved cancer-associated fibroblast (CAF) heterogeneity and discovered that ACTA2 + CAFs sustain MIC identity through a specific ligand-receptor interaction, COL9A1-SDC4. Functional assays confirmed that this axis directly drives the migratory and invasive phenotypes of GC cells.

CONCLUSIONS

This study reveals that metastatic phenotypes may emerge through transcriptional pre-adaptation within primary gastric tumors, orchestrated by a cell-autonomous ETS2 regulatory network governing trajectory progression and sustained by a specialized ACTA2 + CAF niche that maintains MIC identity via COL9A1-SDC4 signaling. These findings suggest a prevention-focused paradigm, identifying the ETS2 circuit and the COL9A1-SDC4 niche axis as complementary candidate targets for intercepting metastasis at its earliest stage.