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Id1 and Id3 Are Regulated Through Matrix‐Assisted Autocrine BMP Signaling and Represent Therapeutic Targets in Melanoma
Author(s) -
Sedlmeier Georg,
AlRawi Vanessa,
Buchert Justyna,
Yserentant Klaus,
Rothley Melanie,
Steshina Anastasia,
Gräßle Simone,
Wu RuoLin,
Hurrle Thomas,
Richer Wilfrid,
Decraene Charles,
Thiele Wilko,
Utikal Jochen,
Abuillan Wasim,
Tanaka Motomu,
Herten DirkPeter,
Hill Caroline S.,
Garvalov Boyan K.,
Jung Nicole,
Bräse Stefan,
Sleeman Jonathan P.
Publication year - 2021
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.202000065
Subject(s) - autocrine signalling , melanoma , matrigel , cancer research , in vivo , extracellular matrix , microbiology and biotechnology , signal transduction , biology , angiogenesis , chemistry , cell culture , genetics
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.