The molecular classification of cancer-associated fibroblasts on a pan-cancer single-cell transcriptional profiling

Backgroud: Cancer-associated fibroblasts (CAFs), a component of the tumor microenvironment, play a critical role in cancer progression, either pro- or anti-tumorigenic functions. Due to the original, phenotypic, and functional heterogeneity, CAFs can be subgrouped into several subpopulations. So far, no molecular classifications of CAFs based on a single-cell pan-cancer scale have been provided. Methods: This study employs a pan-cancer single-cell transcriptional atlas on 9 types of solid tumors (breast cancer, cholangiocarcinoma, colon adenocarcinoma, hepatocellular carcinoma, lung adenocarcinoma, neuroendocrine prostate cancer, pancreatic adenocarcinoma, prostate adenocarcinoma, and stomach adenocarcinoma) to provide a novel molecular classification, elucidate the CAF evolution. The function of each CAF subtype was analyzed by single-cell regulatory network inference and clustering (SCENIC) and single-cell GSEA, and the clinical significance was assessed using survival curves. Furthermore, we used molecular docking to screen small molecules targeting matCAF and conducted in vivo experiments to verify. Results: We distinguished CAFs in the solid tumor as 4 molecular clusters: progenitor CAF (proCAF), inflammatory CAF (iCAF), myofibroblastic CAF (myCAF), and matrix-producing CAF (matCAF) based on the prominent molecular features. The classification is universally applied in all the 9 solid tumors. The 4 CAF subtypes exhibit distinct evolutionary trajectories, functional roles, and clinical significance in different solid tumors. Besides, the matCAF signatures were found to have poor prognoses among multiple cancer types. Targeting matCAF by a screened small molecule, Procyanidin C1, exerted anti-tumor effects in suppressing tumor growth. Conclusions: Together, CAF subtypes play essential roles in cancer initiation and progression, especially mat CAF. Targeting matAF in solid tumors has tumor therapeutic potential.