Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis

J Exp Med. 2022 Jan 3;219(1):e20201039. doi: 10.1084/jem.20201039. Epub 2021 Dec 17.


Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell-induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the γ-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM17 Protein / antagonists & inhibitors*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Biomarkers
  • Biomarkers, Tumor
  • Cell Communication
  • Cell Death
  • Disease Susceptibility / immunology
  • Endothelial Cells / metabolism*
  • Humans
  • Necroptosis* / genetics
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Seeding
  • Neoplasms / etiology*
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Neoplasms / therapy
  • Proteolysis
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • Antineoplastic Agents
  • Biomarkers
  • Biomarkers, Tumor
  • Receptors, Tumor Necrosis Factor, Type I
  • TNFRSF1A protein, human
  • Tumor Necrosis Factor-alpha
  • ADAM17 Protein
  • ADAM17 protein, human