Pan-cancer single-cell analysis identifies a FOXF1/FOXF2-associated transitional CAF-like fibroblast state
Mandzhieva, B.; Verma, A.; Nguyen, T. D. T.; Bang, Y. H.; Park, W. Y.
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Fibroblast heterogeneity shapes tumor progression, yet the transitional states linking normal-associated fibroblasts to cancer-associated fibroblasts (CAFs) remain poorly defined. Here, we integrated single-cell transcriptomic profiles of more than 90,000 stromal cells from 281 samples across nine cancer types to construct a pan-cancer atlas of fibroblast diversity. We identified a distinct CAF-like population positioned between normal-activated fibroblasts and established CAF subsets along the inferred fibroblast activation trajectory. Integration with single-nucleus chromatin accessibility data identified FOXF1 and FOXF2 as candidate regulators of this CAF-like state. Functionally, CAF-like fibroblasts were characterized by non-canonical WNT signaling, WNT5A-associated stromal communication, and a candidate GZMA-F2R/PAR immune-stromal signaling axis supported by spatial transcriptomic analysis. Clinically, the CAF-like signature demonstrated context-dependent prognostic relevance, with high expression associated with poorer survival in the tumor compartment of TCGA stomach adenocarcinoma. Together, this study identifies a FOXF1/FOXF2-associated transitional CAF-like fibroblast state and links it to stromal signaling, immune-stromal communication, and cancer type-specific clinical relevance.
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