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Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.

ABSTRACT: Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3ca(H1047R), a constitutively active mutant of the p110? isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(H1047R)resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs.

SUBMITTER: Castillo SD

PROVIDER: S-EPMC5973268 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.

Castillo Sandra D SD Tzouanacou Elena E Zaw-Thin May M Berenjeno Inma M IM Parker Victoria E R VE Chivite Iñigo I Milà-Guasch Maria M Pearce Wayne W Solomon Isabelle I Angulo-Urarte Ana A Figueiredo Ana M AM Dewhurst Robert E RE Knox Rachel G RG Clark Graeme R GR Scudamore Cheryl L CL Badar Adam A Kalber Tammy L TL Foster Julie J Stuckey Daniel J DJ David Anna L AL Phillips Wayne A WA Lythgoe Mark F MF Wilson Valerie V Semple Robert K RK Sebire Neil J NJ Kinsler Veronica A VA Graupera Mariona M Vanhaesebroeck Bart B

Science translational medicine 20160301 332

Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithf ...[more]

PMID: 27030595

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Project description:BackgroundSporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown.MethodsWe analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples.ResultsWe detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK (mitogen-activated protein kinase)-ERK signaling.ConclusionsWe identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.).

Dataset Information

Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.

Publications

Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.

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