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Id1 and Id3 are regulated through matrix‐assisted autocrine BMP signaling and represent therapeutic targets in melanoma

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journal contribution
posted on 21.04.2021, 10:08 by Georg Sedlmeier, Vanessa Al‐Rawi, Justyna Buchert, Klaus Yserentant, Melanie Rothley, Anastasia Steshina, Simone Gräßle, Ruo‐Lin Wu, Thomas Hurrle, Wilfrid Richer, Charles Decraene, Wilko Thiele, Jochen Utikal, Wasim Abuillan, Motomu Tanaka, Dirk‐Peter Herten, Caroline S Hill, Boyan K Garvalov, Nicole Jung, Stefan Bräse, Jonathan P Sleeman
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.

Funding

Crick (Grant ID: 10095, Grant title: Hill FC001095)

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