A bird’s eye view of fibroblast heterogeneity: A pan-disease, pan-cancer perspective

Fibroblasts, custodians of tissue architecture and function, are no longer considered a monolithic entity across tissues and disease indications. Recent advances in single-cell technologies provide an unrestricted, high-resolution view of fibroblast heterogeneity that exists within and across tissues. In this review, we summarize a compendium of single-cell transcriptomic studies and provide a comprehensive accounting of fibroblast subsets, many of which have been described to occupy specific niches in tissues at homeostatic and pathologic states. Understanding this heterogeneity is particularly important in the context of cancer, as the diverse cancer-associated fibroblast (CAF) phenotypes in the tumor microenvironment (TME) are directly impacted by the expression phenotypes of their predecessors. Relationships between these heterogeneous populations often accompany and influence response to therapy in cancer and fibrosis. We further highlight the importance of integrating single-cell studies to deduce common fibroblast phenotypes across disease states, which will facilitate the identification of common signaling pathways, gene regulatory programs, and cell surface markers that are going to advance drug discovery and targeting.