Meaningful connections: Interrogating the role of physical fibroblast cell-cell communication in cancer.

As part of the connective tissue, activated fibroblasts play an important role in development and disease pathogenesis, while quiescent resident fibroblasts are responsible for sustaining tissue homeostasis. Fibroblastic activation is particularly evident in the tumor microenvironment where fibroblasts transition into tumor-supporting cancer-associated fibroblasts (CAFs), with some CAFs maintaining tumor-suppressive functions. While the tumor-supporting features of CAFs and their fibroblast-like precursors predominantly function through paracrine chemical communication (e.g., secretion of cytokine, chemokine, and more), the direct cell-cell communication that occurs between fibroblasts and other cells, and the effect that the remodeled CAF-generated interstitial extracellular matrix has in these types of cellular communications, remain poorly understood. Here, we explore the reported roles fibroblastic cell-cell communication play within the cancer stroma context and highlight insights we can gain from other disciplines.