Id1 and Id3 Are Regulated Through Matrix‐Assisted Autocrine BMP Signaling and Represent Therapeutic Targets in Melanoma

The tumorigenicity of cancer cells is highly influenced by the extracellular matrix (ECM) through mechanisms that are poorly understood. Here it is reported that a variety of 3D ECM microenvironments strongly induce expression of Id1 and Id3 in melanoma cells. Genetic ablation of Id1/Id3 impairs melanoma cell outgrowth in 3D Matrigel culture and inhibits melanoma initiation in vivo. Mechanistically, 3D ECM microenvironments hinder diffusion of endogenously produced bone morphogenetic proteins, thereby fostering autocrine signaling and Id1/Id3 expression. A compound screen identifies new coumarin derivatives that potently inhibit both Id1/Id3 expression and melanoma initiation in vivo. Together, the findings reveal a novel mechanism through which the ECM increases tumorigenicity, identify Id1/Id3 as melanoma‐relevant therapeutic targets, and characterize inhibitors of Id1/Id3 expression with therapeutic potential. New treatment strategies for melanoma are urgently needed. This study shows that the extracellular matrix can stimulate autocrine bone morphogenetic protein signaling in melanoma cells, leading to upregulation of the transcriptional regulators Id1 and Id3 that promote tumorigenesis. Novel coumarin derivatives are synthesized that inhibit Id1 and Id3 expression and suppress melanoma initiation and growth, representing promising leads for drug development.