The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib
Por:
Kobialka P, Sabata H, Vilalta O, Gouveia L, Angulo-Urarte A, Muixí L, Zanoncello J, Muñoz-Aznar O, Gene-Olaciregui N, Fanlo L, Esteve-Codina A, Lavarino C, Javierre BM, Celis-Passini V, Rovira-Zurriaga C, López-Fernández S, Baselga E, Mora J, CastilloSD and Graupera M
Publicada:
7 jul 2022
Ahead of Print:
1 jun 2022
Categoría:
Molecular medicine
Resumen:
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 Pik3ca(H1047R) 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.
Filiaciones:
Kobialka P:
Endothelial Pathobiology and Microenvironment, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Sabata H:
Endothelial Pathobiology and Microenvironment, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Vilalta O:
Endothelial Pathobiology and Microenvironment, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Gouveia L:
Endothelial Pathobiology and Microenvironment, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
Angulo-Urarte A:
Endothelial Pathobiology and Microenvironment, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Muixí L:
Endothelial Pathobiology and Microenvironment, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Zanoncello J:
Endothelial Pathobiology and Microenvironment, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Muñoz-Aznar O:
Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Gene-Olaciregui N:
Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Fanlo L:
3D Chromatin Organization, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Esteve-Codina A:
CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
Universitat Pompeu Fabra (UPF), Barcelona, Spain
Lavarino C:
Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Javierre BM:
3D Chromatin Organization, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Celis-Passini V:
Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
Rovira-Zurriaga C:
Department of Pathology, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
López-Fernández S:
Department of Plastic Surgery, Hospital de la Santa Creu i de Sant Pau, Barcelona, Spain
Baselga E:
Department of Dermatology, Hospital Sant Joan de Déu, Barcelona, Spain
Mora J:
Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
CastilloSD:
Endothelial Pathobiology and Microenvironment, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
Graupera M:
Endothelial Pathobiology and Microenvironment, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
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