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Contact-dependent signaling triggers tumor-like proliferation of CCM3 knockout endothelial cells in co-culture with wild-type cells
- 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.
Author: | Matthias Rath, Konrad Schwefel, Matteo Malinverno, Dariush Skowronek, Alexandra Leopoldi, Robin A. Pilz, Doreen Biedenweg, Sander BekeschusORCiD, Josef M. Penninger, Elisabetta Dejana, Ute Felbor |
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URN: | urn:nbn:de:gbv:9-opus-107324 |
DOI: | https://doi.org/10.1007/s00018-022-04355-6 |
ISSN: | 1420-9071 |
Parent Title (English): | Cellular and Molecular Life Sciences |
Publisher: | Springer Nature |
Place of publication: | Berlin |
Document Type: | Article |
Language: | English |
Date of first Publication: | 2022/06/04 |
Release Date: | 2024/02/23 |
Tag: | CRISPR/Cas9 genome editing; Cerebral cavernous malformations; Co-culture; NSC59984; RNA sequencing; Tumor-like behavior |
Volume: | 79 |
Issue: | 6 |
Article Number: | 340 |
Page Number: | 20 |
Faculties: | Universitätsmedizin / Institut für Humangenetik |
Collections: | weitere DFG-förderfähige Artikel |
Licence (German): | Creative Commons - Namensnennung 4.0 International |