CC BY 4.0 UnportedRath, MatthiasSchwefel, KonradMalinverno, MatteoSkowronek, DariushLeopoldi, AlexandraPilz, Robin A.Biedenweg, DoreenBekeschus, SanderPenninger, Josef M.Dejana, ElisabettaFelbor, Ute2023-03-062023-03-062022https://oa.tib.eu/renate/handle/123456789/11656http://dx.doi.org/10.34657/10689Cerebral 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.enghttps://creativecommons.org/licenses/by/4.0570610Cerebral cavernous malformationsCo-cultureCRISPR/Cas9 genome editingNSC59984RNA sequencingTumor-like behaviorArticle