Endothelial cell clonal expansion in the development of cerebral cavernous malformations

Matteo Malinverno, Claudio Maderna, Abdallah Abu Taha, Monica Corada, Fabrizio Orsenigo, Mariaelena Valentino, Federica Pisati, Carmela Fusco, Paolo Graziano, Monica Giannotta, Qing Cissy Yu, Yi Arial Zeng, Maria Grazia Lampugnani, Peetra U. Magnusson, Elisabetta Dejana

Research output: Contribution to journalArticle

Abstract

Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers. Here we show that cavernomas originate from clonal expansion of few Ccm3-null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. These characteristics of Ccm3-null cells are reminiscent of the tumour-initiating cells that are responsible for tumour growth. Our data support the concept that CCM has benign tumour characteristics.

Original languageEnglish
Article number2761
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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Central Nervous System Cavernous Hemangioma
Endothelial cells
stem cells
Tumors
Endothelial Cells
Stem cells
Mesenchymal Stromal Cells
markers
Null Lymphocytes
expansion
tumors
Genes
genes
tumor suppressor genes
cells
endothelium
Neoplastic Stem Cells
linings
mutations
Growth

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Malinverno, M., Maderna, C., Abu Taha, A., Corada, M., Orsenigo, F., Valentino, M., ... Dejana, E. (2019). Endothelial cell clonal expansion in the development of cerebral cavernous malformations. Nature Communications, 10(1), [2761]. https://doi.org/10.1038/s41467-019-10707-x

Endothelial cell clonal expansion in the development of cerebral cavernous malformations. / Malinverno, Matteo; Maderna, Claudio; Abu Taha, Abdallah; Corada, Monica; Orsenigo, Fabrizio; Valentino, Mariaelena; Pisati, Federica; Fusco, Carmela; Graziano, Paolo; Giannotta, Monica; Yu, Qing Cissy; Zeng, Yi Arial; Lampugnani, Maria Grazia; Magnusson, Peetra U.; Dejana, Elisabetta.

In: Nature Communications, Vol. 10, No. 1, 2761, 01.12.2019.

Research output: Contribution to journalArticle

Malinverno, M, Maderna, C, Abu Taha, A, Corada, M, Orsenigo, F, Valentino, M, Pisati, F, Fusco, C, Graziano, P, Giannotta, M, Yu, QC, Zeng, YA, Lampugnani, MG, Magnusson, PU & Dejana, E 2019, 'Endothelial cell clonal expansion in the development of cerebral cavernous malformations', Nature Communications, vol. 10, no. 1, 2761. https://doi.org/10.1038/s41467-019-10707-x
Malinverno M, Maderna C, Abu Taha A, Corada M, Orsenigo F, Valentino M et al. Endothelial cell clonal expansion in the development of cerebral cavernous malformations. Nature Communications. 2019 Dec 1;10(1). 2761. https://doi.org/10.1038/s41467-019-10707-x
Malinverno, Matteo ; Maderna, Claudio ; Abu Taha, Abdallah ; Corada, Monica ; Orsenigo, Fabrizio ; Valentino, Mariaelena ; Pisati, Federica ; Fusco, Carmela ; Graziano, Paolo ; Giannotta, Monica ; Yu, Qing Cissy ; Zeng, Yi Arial ; Lampugnani, Maria Grazia ; Magnusson, Peetra U. ; Dejana, Elisabetta. / Endothelial cell clonal expansion in the development of cerebral cavernous malformations. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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