Multifaceted collagen-DDR1 signaling in cancer.

Discoidin domain receptor 1 (DDR1) is an important signal transducer that mediates crosstalk between cancer cells and their surrounding stroma. Due to the very high concentrations of its ligand, cleaved collagen (COL), DDR1 exerts a profound effect on tumor metabolism. DDR1 controls macropinocytosis–autophagy crosstalk by activating NRF2, a key transcriptional regulator of metabolic adaptation. Distinct COL types and their cleavage products exert differential effects on DDR1 activity and expression. DDR1 is an interesting therapeutic target for those cancers whose metabolism and growth depend on its activation. In addition to immune cells and fibroblasts, the tumor microenvironment (TME) comprises an extracellular matrix (ECM) which contains collagens (COLs) whose architecture and remodeling dictate cancer development and progression. COL receptors expressed by cancer cells sense signals generated by microenvironmental alterations in COL state to regulate cell behavior and metabolism. Discoidin domain receptor 1 (DDR1) is a key sensor of COL fiber state and composition that controls tumor cell metabolism and growth, response to therapy, and patient survival. This review focuses on DDR1 to NRF2 signaling, its modulation of autophagy and macropinocytosis (MP), and its role in cancer and other diseases. Elucidating the regulation of DDR1 activity and expression under different pathophysiological conditions will facilitate the discovery of new therapeutics. [ABSTRACT FROM AUTHOR]