Active remodeling of capillary endothelium via cancer cell-derived MMP9 promotes metastatic brain colonization

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Matthia A. Karreman - , Heidelberg University , German Cancer Research Center (DKFZ), European Molecular Biology Laboratory (EMBL) Heidelberg (Author)
  • Alexander T. Bauer - , University of Hamburg (Author)
  • Gergely Solecki - , Heidelberg University , German Cancer Research Center (DKFZ), Carl Zeiss AG (Author)
  • Anna S. Berghoff - , Heidelberg University , German Cancer Research Center (DKFZ), Medical University of Vienna (Author)
  • Chanté D. Mayer - , Heidelberg University , German Cancer Research Center (DKFZ) (Author)
  • Katharina Frey - , Heidelberg University , German Cancer Research Center (DKFZ) (Author)
  • Nils Hebach - , Heidelberg University , German Cancer Research Center (DKFZ) (Author)
  • Manuel J. Feinauer - , Heidelberg University , German Cancer Research Center (DKFZ) (Author)
  • Nicole L. Schieber - , European Molecular Biology Laboratory (EMBL) Heidelberg, University of Queensland (Author)
  • Cedric Tehranian - , German Cancer Research Center (DKFZ) (Author)
  • Luc Mercier - , University of Strasbourg (Author)
  • Mahak Singhal - , Heidelberg University , German Cancer Research Center (DKFZ) (Author)
  • Varun Venkataramani - , Heidelberg University , German Cancer Research Center (DKFZ) (Author)
  • Marc C. Schubert - , Heidelberg University  (Author)
  • Daniel Hinze - , LAMPseq Diagnostics GmbH, University of Bonn (Author)
  • Michael Hölzel - , University of Bonn (Author)
  • Iris Helfrich - , University of Duisburg-Essen, German Cancer Research Center (DKFZ), Ludwig Maximilian University of Munich (Author)
  • Dirk Schadendorf - , University of Duisburg-Essen, German Cancer Research Center (DKFZ) (Author)
  • Stefan W. Schneider - , University of Hamburg (Author)
  • Dana Westphal - , Department of Dermatology, National Center for Tumor Diseases (Partners: UKD, MFD, HZDR, DKFZ) (Author)
  • Hellmut G. Augustin - , Heidelberg University , German Cancer Research Center (DKFZ) (Author)
  • Jacky G. Goetz - , University of Strasbourg (Author)
  • Yannick Schwab - , European Molecular Biology Laboratory (EMBL) Heidelberg (Author)
  • Wolfgang Wick - , Heidelberg University , German Cancer Research Center (DKFZ) (Author)
  • Frank Winkler - , Heidelberg University , German Cancer Research Center (DKFZ) (Author)

Abstract

Crossing the blood-brain barrier is a crucial, rate-limiting step of brain metastasis. Understanding of the mechanisms of cancer cell extravasation from brain microcapillaries is limited as the underlying cellular and molecular processes cannot be adequately investigated using in vitro models and end-point in vivo experiments. Using ultrastructural and functional imaging, we demonstrate that dynamic changes of activated brain microcapillaries promote the mandatory first steps of brain colonization. Successful extravasation of arrested cancer cells occurred when adjacent capillary endothelial cells (ECs) entered into a distinct remodeling process. After extravasation, capillary loops were formed, which was characteristic of aggressive metastatic growth. Upon cancer cell arrest in brain microcapillaries, matrix-metalloprotease 9 (MMP9) was expressed. Inhibition of MMP2/9 and genetic perturbation of MMP9 in cancer cells, but not the host, reduced EC projections, extravasation, and brain metastasis outgrowth. These findings establish an active role of ECs in the process of cancer cell extravasation, facilitated by crosstalk between the two cell types. This extends our understanding of how host cells can contribute to brain metastasis formation and how to prevent it.

Details

Original languageEnglish
Pages (from-to)1299-1314
Number of pages16
JournalCancer research
Volume83
Issue number8
Publication statusPublished - 15 Apr 2023
Peer-reviewedYes

External IDs

PubMed 36652557
ORCID /0000-0003-4340-0402/work/145223804

Keywords

Sustainable Development Goals

ASJC Scopus subject areas

Keywords

  • brain metastasis, endothelial remodeling, extravasation, intravital microscopy, matrix metalloproteinase, Brain/pathology, Endothelium, Vascular/pathology, Endothelial Cells/metabolism, Matrix Metalloproteinase 9/metabolism, Humans, Cell Line, Tumor, Brain Neoplasms/pathology