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Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation

Author

Listed:
  • Ines Martinez-Corral

    (Uppsala University, Department of Immunology, Genetics and Pathology)

  • Yan Zhang

    (Uppsala University, Department of Immunology, Genetics and Pathology)

  • Milena Petkova

    (Uppsala University, Department of Immunology, Genetics and Pathology)

  • Henrik Ortsäter

    (Uppsala University, Department of Immunology, Genetics and Pathology)

  • Sofie Sjöberg

    (Uppsala University, Department of Immunology, Genetics and Pathology)

  • Sandra D. Castillo

    (Vascular Signaling Laboratory, Institut d´Investigació Biomèdica de Bellvitge (IDIBELL), 08908L´Hospitalet de Llobregat)

  • Pascal Brouillard

    (University of Louvain)

  • Louis Libbrecht

    (University of Louvain)

  • Dieter Saur

    (Technische Universität München)

  • Mariona Graupera

    (Vascular Signaling Laboratory, Institut d´Investigació Biomèdica de Bellvitge (IDIBELL), 08908L´Hospitalet de Llobregat)

  • Kari Alitalo

    (FIN-00014 University of Helsinki)

  • Laurence Boon

    (University of Louvain
    University of Louvain)

  • Miikka Vikkula

    (University of Louvain
    University of Louvain)

  • Taija Mäkinen

    (Uppsala University, Department of Immunology, Genetics and Pathology)

Abstract

Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CAH1047R mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CAH1047R-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110α activation determining the LM subtype. In the postnatal vasculature, PIK3CAH1047R promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways.

Suggested Citation

  • Ines Martinez-Corral & Yan Zhang & Milena Petkova & Henrik Ortsäter & Sofie Sjöberg & Sandra D. Castillo & Pascal Brouillard & Louis Libbrecht & Dieter Saur & Mariona Graupera & Kari Alitalo & Laurenc, 2020. "Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16496-y
    DOI: 10.1038/s41467-020-16496-y
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    Cited by:

    1. Nieves Montenegro-Navarro & Claudia García-Báez & Melissa García-Caballero, 2023. "Molecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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