Cancer-associated fibroblasts recapitulate phenotypes and functions across tumor types and species

Cancer-associated fibroblasts (CAFs) are among the most abundant cell types in desmoplastic tumors. However, CAFs are not yet a treatment target in mainstream cancer therapy likely because CAF heterogeneity and their roles in solid tumors remain incompletely understood. Here, we explored CAF heterogeneity via single-cell gene expression and chromatin accessibility in conjunction with spatial transcriptomics. We found that CAF heterogeneity is recapitulated across solid tumor types and species, and CAF subpopulations fall into two functional categories: mechano-responsive and immuno-modulatory. These categories are spatially-distinct and governed by specific changes in chromatin accessibility. Selective disruption of underlying mechanical force or immune signaling results in predictable shifts in subpopulation distributions and impacts tumor growth. Collectively, this research elucidates the spatial dynamics of CAF biology, delineates CAF subpopulation functions, identifies CAF-specific treatment factors, and provides a multimodal -omics framework for understanding the tumor stromal niche. Overall design: Mouse tumor tissue samples were profiled using single-cell RNA sequencing and single-cell ATAC sequencing. Tissue was obtained from mouse endogenous breast tumors. Human tumor tissue samples were obtained from core needle biopsies for breast cancer and from Whipple procedures for pancreatic cancer. Human tissue samples were profiled using single-cell RNA sequencing.