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

Research output: Contribution to journalArticlepeer-review

Authors

  • Georg Sedlmeier
  • Vanessa Al-Rawi
  • Justyna Buchert
  • Melanie Rothley
  • Anastasia Steshina
  • Simone Gräßle
  • Rou-Lin Wu
  • Thomas Hurrle
  • Wilfrid Richer
  • Charles Decraene
  • Wilko Thiele
  • Jochen Utikal
  • Wasim Abuillan
  • Motomu Tanaka
  • Caroline S. Hill
  • Boyan K. Garvalov
  • Nicole Jung
  • Stefan Bräse
  • Jonathan P. Sleeman

Colleges, School and Institutes

External organisations

  • Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim of the University of Heidelberg, Ludolf‐Krehl‐Strasse 13–17, 68167 Mannheim, Germany
  • European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • Institute of Biological and Chemical Systems – Biological Information Processing (IBCS‐BIP), Karlsruhe Institute of Technology, Campus North, Building 319, Hermann‐von‐Helmholtz‐Platz 1, 76344 Eggenstein‐Leopoldshafen, Germany
  • Institute of Organic Chemistry (IOC), Karlsruhe Institute of Technology, Campus South, Building 30.42, Fritz‐Haber‐Weg 6, 76131 Karlsruhe, Germany
  • Institute of Biological and Chemical Systems – Functional Molecular Systems (IBCS‐FMS), Karlsruhe Institute of Technology (KIT), Hermann‐von‐Helmholtz‐Platz 1, D‐76344 Eggenstein‐Leopoldshafen, Germany
  • Institute of Organic Chemistry (IOC), Karlsruhe Institute of Technology, Campus South, Building 30.42, Fritz‐Haber‐Weg 6, 76131 Karlsruhe, Germany
  • CNRS UMR144, Translational Research Department, Institut Curie, PSL Research University, 26 rue d'Ulm, Paris Cedex 05, 75248 France
  • Institute of Biological and Chemical Systems – Biological Information Processing (IBCS‐BIP), Karlsruhe Institute of Technology, Campus North, Building 319, Hermann‐von‐Helmholtz‐Platz 1, 76344 Eggenstein‐Leopoldshafen, Germany
  • Skin Cancer Unit, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht‐Karl University of Heidelberg, Theodor‐Kutzer‐Ufer 1–3, 68167 Mannheim, Germany
  • Institute of Physical Chemistry, University of Heidelberg, Im Neuenheimer Feld 253, 69120 Heidelberg, Germany.
  • Center for Integrative Medicine and Physics, Institute for Advanced Study, Kyoto University, Yoshida Ushinomiya‐cho, Sakyo‐Ku, Kyoto, 606‐8501 Japan
  • Center for Integrative Medicine and Physics, Institute for Advanced Study, Kyoto University, Kyoto, 606‐8501 Japan
  • The Francis Crick Institute, London

Abstract

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.

Details

Original languageEnglish
Article number2000065
Number of pages17
JournalAdvanced Therapeutics
Publication statusPublished - 12 Oct 2020