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The extracellular matrix and the clonogenic survival benefit of CCM3-/- endothelial cells as new therapeutic targets for cerebral cavernous malformations

Subject Area Molecular Biology and Physiology of Neurons and Glial Cells
Human Genetics
Term from 2017 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 383067719
 
Final Report Year 2023

Final Report Abstract

Cerebral cavernous malformations (CCMs) can lead to seizures, paralysis, or speech disturbances. The hereditary form of CCM is a rare disease. Yet, there are probably more than two million people worldwide with hereditary CCM disease. Especially patients with pathogenic CCM3 variants often present with an early age of onset and a more severe course of the disease. Following the 3R principle, we here reproduced known characteristics of the complex CCM pathogenesis by CRISPR/Cas9- mediated inactivation of the CCM3 gene in human endothelial cells (ECs). In addition, we demonstrated that CCM3 inactivation interferes with the expression of the important matrix component fibronectin. Supplementation of fibronectin normalized cell morphology, actin cytoskeleton alignment, and EC organization into three-dimensional spheroids, but not characteristic gene expression differences in CCM3-deficient ECs. In agreement with recent observations from CCM mouse models, our study also shed light on a new aspect of CCM pathogenesis. CCMs are not malignant tumors. Nevertheless, our results showed that "tumor-like" mechanisms play a role in disease development. CCM3- deficient ECs demonstrated an abnormally strong proliferation when they came into contact with wildtype cells. We also tested an apoptosis-modulating drug library and found that NSC59984, a drug previously described only in the cancer context, can effectively inhibit the abnormal proliferation of the mutant cells. The project results thus fit very well into the current trend in international research on vascular malformations, in which the repurposing of anticancer drugs is being intensively discussed as a new therapeutic approach. Since mutant ECs exist in a mosaic pattern with wild-type or heterozygous ECs in CCMs, the results of our RNA sequencing from co-cultures are also relevant, as they show that the two cell types intensively influence each other at the molecular level. A better understanding of the interaction of these cells will be one of the main tasks on the way for the development of targeted CCM therapies.

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