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Endothelial cell clonal expansion in the development of cerebral cavernous malformations

Author

Listed:
  • Matteo Malinverno

    (The FIRC Institute of Molecular Oncology Foundation)

  • Claudio Maderna

    (The FIRC Institute of Molecular Oncology Foundation)

  • Abdallah Abu Taha

    (Uppsala University)

  • Monica Corada

    (The FIRC Institute of Molecular Oncology Foundation)

  • Fabrizio Orsenigo

    (The FIRC Institute of Molecular Oncology Foundation)

  • Mariaelena Valentino

    (The FIRC Institute of Molecular Oncology Foundation)

  • Federica Pisati

    (The FIRC Institute of Molecular Oncology Foundation
    Cogentech S.c.a.r.l)

  • Carmela Fusco

    (Fondazione IRCCS-Casa Sollievo della Sofferenza)

  • Paolo Graziano

    (Fondazione IRCCS-Casa Sollievo della Sofferenza)

  • Monica Giannotta

    (The FIRC Institute of Molecular Oncology Foundation)

  • Qing Cissy Yu

    (Chinese Academy of Sciences)

  • Yi Arial Zeng

    (Chinese Academy of Sciences)

  • Maria Grazia Lampugnani

    (The FIRC Institute of Molecular Oncology Foundation
    Mario Negri Institute for Pharmacological Research)

  • Peetra U. Magnusson

    (Uppsala University)

  • Elisabetta Dejana

    (The FIRC Institute of Molecular Oncology Foundation
    Uppsala University
    University of Milan)

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.

Suggested Citation

  • Matteo Malinverno & Claudio Maderna & Abdallah Abu Taha & Monica Corada & Fabrizio Orsenigo & Mariaelena Valentino & Federica Pisati & Carmela Fusco & Paolo Graziano & Monica Giannotta & Qing Cissy Yu, 2019. "Endothelial cell clonal expansion in the development of cerebral cavernous malformations," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10707-x
    DOI: 10.1038/s41467-019-10707-x
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    Cited by:

    1. Apeksha Shapeti & Jorge Barrasa-Fano & Abdel Rahman Abdel Fattah & Janne Jong & José Antonio Sanz-Herrera & Mylène Pezet & Said Assou & Emilie Vet & Seyed Ali Elahi & Adrian Ranga & Eva Faurobert & Ha, 2024. "Force-mediated recruitment and reprogramming of healthy endothelial cells drive vascular lesion growth," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Haifeng Zhang & Busu Li & Qunhua Huang & Francesc López-Giráldez & Yoshiaki Tanaka & Qun Lin & Sameet Mehta & Guilin Wang & Morven Graham & Xinran Liu & In-Hyun Park & Anne Eichmann & Wang Min & Jenny, 2022. "Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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