The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib

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  • dc.contributor.author Kobialka, Piotr
  • dc.contributor.author Sabata, Helena
  • dc.contributor.author Vilalta, Odena
  • dc.contributor.author Gouveia, Leonor
  • dc.contributor.author Angulo-Urarte, Ana
  • dc.contributor.author Muixí, Laia
  • dc.contributor.author Zanoncello, Jasmina
  • dc.contributor.author Muñoz-Aznar, Oscar
  • dc.contributor.author Olaciregui, Nagore G.
  • dc.contributor.author Fanlo, Lucía
  • dc.contributor.author Esteve-Codina, Anna
  • dc.contributor.author Lavarino, Cinzia
  • dc.contributor.author Javierre, Biola M.
  • dc.contributor.author Celis-Passini, Veronica Paola
  • dc.contributor.author Rovira, Carlota
  • dc.contributor.author López-Fernández, Susana
  • dc.contributor.author Baselga, Eulàlia
  • dc.contributor.author Mora, Jaume
  • dc.contributor.author Castillo, Sandra D.
  • dc.contributor.author Graupera, Mariona
  • dc.date.accessioned 2022-10-27T06:03:14Z
  • dc.date.available 2022-10-27T06:03:14Z
  • dc.date.issued 2022
  • dc.description.abstract Low-flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we demonstrate that the Pik3caH1047R activating mutation in endothelial cells triggers a transcriptome rewiring that leads to enhanced cell proliferation. We describe a new reproducible preclinical in vivo model of PI3K-driven vascular malformations using the postnatal mouse retina. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activating Pik3ca mutations. Using this model, we demonstrate that the AKT inhibitor miransertib both prevents and induces the regression of PI3K-driven vascular malformations. We confirmed the efficacy of miransertib in isolated human endothelial cells with genotypes spanning most of human low-flow vascular malformations.
  • dc.description.sponsorship The research leading to these results has received funding by the Spanish Ministry of Science and Innovation MICINN (PID2020-116184RB-I00 /AEI/10.13038/501100011033). M.G. laboratory is supported by the research grants SAF2017-89116R-P (FEDER/EU) from MCIU (Spain) co-funded by European Regional Developmental Fund (ERDF), a Way to Build Europe and PID2020-116184RB-I00 from MCEI; PTEN RESEARCH Foundation (IJC-21-001); la Caixa Banking Foundation (LCF/PR/PR16/51110035 and LCF/PR/HR19/52160023; also to E.B. and J.M.); by la Asociación Española contra el Cancer (AECC)-Grupos Traslacionales (GCTRA18006CARR); by la Fundación BBVA (Ayuda Fundación BBVA a Equipos de Investigación Científica 2019); World Cancer Research (21-0159). The computations and data handling were enabled by resources in projects SNIC 2019/30-26 and SNIC 2019/8-129, provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. Personal support was from Marie-Curie ITN Actions (P.K. and J.Z.) grant agreement 675392. L.G. is funded by the Swedish Research Council (2018-06591). S.D.C. is a recipient of a fellowship from the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement No 749731. S.D.C. is currently funded by la Caixa Banking Foundation Junior Leader project (LCF/BQ/PR20/11770002). E.B. is funded by the Agencia Estatal de Investigación (Proyectos de investigación en salud PI20/00102).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Kobialka P, Sabata H, Vilalta O, Gouveia L, Angulo-Urarte A, Muixí L, Zanoncello J, Muñoz-Aznar O, Olaciregui NG, Fanlo L, Esteve-Codina A, Lavarino C, Javierre BM, Celis V, Rovira C, López-Fernández S, Baselga E, Mora J, Castillo SD, Graupera M. The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib. EMBO Mol Med. 2022 Jul 7;14(7):e15619. DOI: 10.15252/emmm.202115619
  • dc.identifier.doi http://dx.doi.org/10.15252/emmm.202115619
  • dc.identifier.issn 1757-4676
  • dc.identifier.uri http://hdl.handle.net/10230/54619
  • dc.language.iso eng
  • dc.publisher Wiley
  • dc.relation.ispartof EMBO Mol Med. 2022 Jul 7;14(7):e15619
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/675392
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-116184RB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-89116R-P
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/749731
  • dc.rights © 2022 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri https://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword AKT
  • dc.subject.keyword PI3K
  • dc.subject.keyword Angiogenesis
  • dc.subject.keyword Endothelial cell
  • dc.subject.keyword Vascular malformations
  • dc.title The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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