Contact-dependent signaling triggers tumor-like proliferation of CCM3 knockout endothelial cells in co-culture with wild-type cells
| Autor: | Matthias Rath, Konrad Schwefel, Matteo Malinverno, Dariush Skowronek, Alexandra Leopoldi, Robin A. Pilz, Doreen Biedenweg, Sander Bekeschus, Josef M. Penninger, Elisabetta Dejana, Ute Felbor |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
Hemangioma Cavernous Central Nervous System Cas9 genome editing Cellbiologi Cerebral cavernous malformations Endothelial Cells RNA sequencing Cell Biology Coculture Techniques NSC59984 Cellular and Molecular Neuroscience Proto-Oncogene Proteins CRISPR Humans Molecular Medicine Co-culture Apoptosis Regulatory Proteins Molecular Biology Tumor-like behavior Cell Proliferation |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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