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

Ines Martinez-Corral, Yan Zhang, Milena Petkova, Henrik Ortsäter, Sofie Sjöberg, Sandra D. Castillo, Pascal Brouillard, Louis Libbrecht, Dieter Saur, Mariona Graupera, Kari Alitalo, Laurence Boon, Miikka Vikkula and Taija Mäkinen ()
Additional contact information
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
Miikka Vikkula: University of Louvain
Taija Mäkinen: Uppsala University, Department of Immunology, Genetics and Pathology

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-020-16496-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16496-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-16496-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().