TY - JOUR
T1 - Id1 and Id3 Are Regulated Through Matrix‐Assisted Autocrine BMP Signaling and Represent Therapeutic Targets in Melanoma
AU - Sedlmeier, Georg
AU - Al-Rawi, Vanessa
AU - Buchert, Justyna
AU - Yserentant, Klaus
AU - Rothley, Melanie
AU - Steshina, Anastasia
AU - Gräßle, Simone
AU - Wu, Rou-Lin
AU - Hurrle, Thomas
AU - Richer, Wilfrid
AU - Decraene, Charles
AU - Thiele, Wilko
AU - Utikal, Jochen
AU - Abuillan, Wasim
AU - Tanaka, Motomu
AU - Herten, Dirk-Peter
AU - Hill, Caroline S.
AU - Garvalov, Boyan K.
AU - Jung, Nicole
AU - Bräse, Stefan
AU - Sleeman, Jonathan P.
PY - 2020/10/12
Y1 - 2020/10/12
N2 - 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.
AB - 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.
U2 - 10.1002/adtp.202000065
DO - 10.1002/adtp.202000065
M3 - Article
SN - 2366-3987
JO - Advanced Therapeutics
JF - Advanced Therapeutics
M1 - 2000065
ER -
