Journal article

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

Sandra D Castillo, Elena Tzouanacou, May Zaw-Thin, Inma M Berenjeno, Victoria ER Parker, Inigo Chivite, Maria Mila-Guasch, Wayne Pearce, Isabelle Solomon, Ana Angulo-Urarte, Ana M Figueiredo, Robert E Dewhurst, Rachel G Knox, Graeme R Clark, Cheryl L Scudamore, Adam Badar, Tammy L Kalber, Julie Foster, Daniel J Stuckey, Anna L David Show all

SCIENCE TRANSLATIONAL MEDICINE | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2016

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 p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial e..

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Grants

Awarded by EMBO


Awarded by European Union (EU) Marie Curie


Awarded by EU Marie Curie


Awarded by Engineering and Physical Sciences Research Council (EPSRC) Early Career Fellowship of T.L.K.


Awarded by Wellcome Trust


Awarded by Medical Research Council (MRC)


Awarded by MINECO (Spain)


Awarded by Catalan Government


Awarded by People Programme (Marie Curie Actions) from the EU's Seventh Framework Programme FP7


Awarded by European Regional Development Fund (ERDF) under the integrated Project of Excellence


Awarded by Cancer Research UK


Awarded by Biotechnology and Biological Sciences Research Council


Awarded by British Heart Foundation


Awarded by Engineering and Physical Sciences Research Council


Awarded by Medical Research Council


Awarded by National Institute for Health Research


Awarded by EPSRC


Awarded by MRC


Funding Acknowledgements

Postdoctoral fellowships were from EMBO (ALTF 165-2013) to S.D.C., European Union (EU) Marie Curie (MEIF-CT-2005-010264) to E.T., and EU Marie Curie (PIIF-GA-2009-252846) to I.M.B. M.Z.-T. is supported by the Engineering and Physical Sciences Research Council (EPSRC) Early Career Fellowship of T.L.K. (EP/L006472/1). D.J.S. is a British Heart Foundation (BHF) Intermediate Basic Science Research Fellow (FS/15/33/31608). A.L.D. is supported by the UK National Institute for Health Research (NIHR) Joint UCL/University College London Hospitals Biomedical Research Centre. V.E.R.P. was supported by the Wellcome Trust (097721/Z/11/Z). R.K.S. is supported by the Wellcome Trust (WT098498), the Medical Research Council (MRC) (MRC_MC_UU_12012/5), and the NIHR Rare Diseases Translational Research Collaboration. R.G.K. is supported by the NIHR Rare Diseases Translational Research Collaboration. N.J.S. is partly supported by the NIHR GOSH BRC and GOSHCC. V.A.K. is funded by the Wellcome Trust, award number WT104076MA. V.W. was supported by the European Framework Programme VI (FPVI) Integrated Project "Eurostemcell." M.F.L. and A.B. are supported by the King's College London and UCL Comprehensive Cancer Imaging Centre Cancer Research UK and EPSRC, in association with the MRC and Department of Health (England). W.A.P. is supported by funding from the National Health and Medical Research Council (NHMRC) of Australia. Work in the laboratory of M.G. is supported by research grants SAF2013-46542-P and SAF2014-59950-P from MINECO (Spain), 2014-SGR-725 from the Catalan Government, the People Programme (Marie Curie Actions) from the EU's Seventh Framework Programme FP7/2007-2013/(REA grant agreement 317250), the Institute of Health Carlos III (ISC III), and the European Regional Development Fund (ERDF) under the integrated Project of Excellence no. PIE13/00022 (ONCOPROFILE). Work in the laboratory of B.V. is supported by Cancer Research UK (C23338/A15965) and the UK NIHR University College London Hospitals Biomedical Research Centre.