Key result
FAP+ cancer-associated fibroblasts orchestrate an immunosuppressive stem cell niche in colon cancer, and a derived 14-gene prognostic risk model demonstrated predictive accuracy with an AUC > 0.64.
Why the study?
Although FAP is highly expressed in CAFs and linked to poor prognosis in colon cancer, its role in coordinating immune evasion and cancer stemness remains to be fully elucidated.
Observational
Effect estimate: AUC > 0.64
FAP+ CAFs orchestrate an immunosuppressive stem cell niche in colon cancer, and a 14-gene prognostic model based on these findings shows predictive value.
Suggests FAP+ CAFs as potential therapeutic target in colon cancer; leaves open clinical validation of the COL1A1/2-CD44 axis.
Background: Colon cancer (CC) remains a leading cause of cancer-related mortality worldwide, driven largely by the complex interactions within the tumor microenvironment (TME). Fibroblast activation protein (FAP) is highly expressed in cancer-associated fibroblasts (CAFs) and is associated with poor prognosis, yet its role in coordinating immune evasion and cancer stemness remains to be fully elucidated. Methods: We integrated multiomics data from TCGA and GEO databases, utilizing bulk RNA-seq and single-cell RNA-seq (scRNA-seq) analyses. Findings were validated via tissue microarray (TMA) immunohistochemistry (IHC). We further employed cell-cell communication analysis, pseudotime trajectory modeling, and the Connectivity Map (CMap) for drug sensitivity prediction and molecular docking. Results: FAP was significantly upregulated in CC tissues and correlated with advanced clinical stages. scRNA-seq confirmed that FAP is predominantly expressed in CAFs. Functional analysis revealed that FAP-high tumors are enriched in extracellular matrix (ECM) remodeling and immunosuppressive pathways. Cell-cell communication analysis identified that FAP+ CAFs interact with T cells and cancer stem cells (CSCs) primarily through the COL1A1/2-CD44 axis. Specifically, FAP+ CAFs promote the differentiation of naive T cells into regulatory T cells (Tregs) and are positively correlated with various stemness markers, including CD44, ABCG2, and BMI1. Based on these findings, we established a 14-gene prognostic risk model with robust predictive accuracy (area under the curve [AUC] > 0.64) and identified AS604850 and LY364947 as potential therapeutic agents. Conclusion: Our study demonstrates that FAP+ CAFs orchestrate a dual-functional "immunosuppressive stem cell niche" via the COL1A1/2-CD44 signaling axis. Targeting this FAP-driven niche provides a promising strategy for overcoming immunotherapy resistance and improving clinical outcomes in CC.
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Ding et al. (2026) conducted an observational in Colon cancer. FAP expression in cancer-associated fibroblasts was evaluated on Prognostic risk model predictive accuracy (AUC > 0.64). FAP+ cancer-associated fibroblasts orchestrate an immunosuppressive stem cell niche in colon cancer, and a derived 14-gene prognostic risk model demonstrated predictive accuracy with an AUC > 0.64.
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