2. Academic Validation
  3. Contact-dependent signaling triggers tumor-like proliferation of CCM3 knockout endothelial cells in co-culture with wild-type cells

Contact-dependent signaling triggers tumor-like proliferation of CCM3 knockout endothelial cells in co-culture with wild-type cells

  • Cell Mol Life Sci. 2022 Jun 4;79(6):340. doi: 10.1007/s00018-022-04355-6.
Matthias Rath  # 1,  Konrad Schwefel  # 2,  Matteo Malinverno 3,  Dariush Skowronek 2,  Alexandra Leopoldi 4,  Robin A Pilz 2,  Doreen Biedenweg 5,  Sander Bekeschus 6,  Josef M Penninger 4 7,  Elisabetta Dejana 3 8,  Ute Felbor 2
Affiliations

Affiliations

  • 1 Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Fleischmannstraße 43, 17475, Greifswald, Germany. matthias.rath@med.uni-greifswald.de.
  • 2 Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Fleischmannstraße 43, 17475, Greifswald, Germany.
  • 3 Vascular Biology Unit, FIRC Institute of Molecular Oncology Foundation (IFOM), Milan, Italy.
  • 4 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
  • 5 Centre for Innovation Competence-Humoral Immune Reactions in Cardiovascular Diseases, University of Greifswald, Greifswald, Germany.
  • 6 ZIK Plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Greifswald, Germany.
  • 7 Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
  • 8 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
  • # Contributed equally.
PMID: 35661927 DOI: 10.1007/s00018-022-04355-6
Abstract

Cerebral cavernous malformations (CCM) are low-flow vascular lesions prone to cause severe hemorrhage-associated neurological complications. Pathogenic germline variants in CCM1, CCM2, or CCM3 can be identified in nearly 100% of CCM patients with a positive family history. In line with the concept that tumor-like mechanisms are involved in CCM formation and growth, we here demonstrate an abnormally increased proliferation rate of CCM3-deficient endothelial cells in co-culture with wild-type cells and in mosaic human iPSC-derived vascular organoids. The observation that NSC59984, an Anticancer drug, blocked the abnormal proliferation of mutant endothelial cells further supports this intriguing concept. Fluorescence-activated cell sorting and RNA Sequencing revealed that co-culture induces upregulation of proangiogenic chemokine genes in wild-type endothelial cells. Furthermore, genes known to be significantly downregulated in CCM3-/- endothelial cell mono-cultures were upregulated back to normal levels in co-culture with wild-type cells. These results support the hypothesis that wild-type ECs facilitate the formation of a niche that promotes abnormal proliferation of mutant ECs. Thus, targeting the cancer-like features of CCMs is a promising new direction for drug development.

Keywords

CRISPR/Cas9 genome editing; Cerebral cavernous malformations; Co-culture; NSC59984; RNA sequencing; Tumor-like behavior.

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