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1.
Cancer Gene Ther ; 30(8): 1114-1123, 2023 08.
Article in English | MEDLINE | ID: mdl-37188724

ABSTRACT

Despite their rarity, PIK3CA mutations in meningiomas have raised interest as potentially targetable, ubiquitous mutations owing to their presence in sporadic benign and malignant tumors but also in hormone-related cases. Using new genetically engineered mouse models, we here demonstrate that Pik3ca mutations in postnatal meningeal cells are sufficient to promote meningioma formation but also tumor progression in mice. Conversely, hormone impregnation, whether alone or in association with Pik3ca and Nf2 mutations, fails to induce meningioma tumorigenesis while promoting breast tumor formation. We then confirm in vitro the effect of Pik3ca mutations but not hormone impregnation on the proliferation of primary cultures of mouse meningeal cells. Finally, we show by exome analysis of breast tumors and meninges that hormone impregnation promotes breast tumor formation without additional somatic oncogenic mutation but is associated with an increased mutational burden on Pik3ca-mutant background. Taken together, these results tend to suggest a prominent role of Pik3ca mutations over hormone impregnation in meningioma tumorigenesis, the exact effect of the latter is still to be discovered.


Subject(s)
Breast Neoplasms , Meningeal Neoplasms , Meningioma , Mice , Animals , Humans , Female , Meningioma/genetics , Meningioma/pathology , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Cyproterone Acetate , Mutation , Cell Transformation, Neoplastic , Class I Phosphatidylinositol 3-Kinases/genetics
2.
Sci Adv ; 8(49): eade7823, 2022 12 09.
Article in English | MEDLINE | ID: mdl-36490341

ABSTRACT

PIK3CA-related overgrowth syndrome (PROS) is a genetic disorder caused by somatic mosaic gain-of-function mutations of PIK3CA. Clinical presentation of patients is diverse and associated with endocrine disruption. Adipose tissue is frequently involved, but its role in disease development and progression has not been elucidated. Here, we created a mouse model of PIK3CA-related adipose tissue overgrowth that recapitulates patient phenotype. We demonstrate that PIK3CA mutation leads to GLUT4 membrane accumulation with a negative feedback loop on insulin secretion, a burst of liver IGFBP1 synthesis with IGF-1 sequestration, and low circulating levels. Mouse phenotype was mainly driven through AKT2. We also observed that PIK3CA mutation induces metabolic reprogramming with Warburg-like effect and protein and lipid synthesis, hallmarks of cancer cells, in vitro, in vivo, and in patients. We lastly show that alpelisib is efficient at preventing and improving PIK3CA-adipose tissue overgrowth and reversing metabolomic anomalies in both animal models and patients.


Subject(s)
Adipose Tissue , Class I Phosphatidylinositol 3-Kinases , Gain of Function Mutation , Animals , Mice , Adipose Tissue/metabolism , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/metabolism , Gain of Function Mutation/genetics , Mutation , Phenotype
3.
Sci Transl Med ; 13(614): eabg0809, 2021 Oct 06.
Article in English | MEDLINE | ID: mdl-34613809

ABSTRACT

Lymphatic cystic malformations are rare genetic disorders mainly due to somatic gain-of-function mutations in the PIK3CA gene. These anomalies are frequently associated with pain, inflammatory flares, esthetic deformities, and, in severe forms, life-threatening conditions. There is no approved medical therapy for patients with lymphatic malformations. In this proof-of-concept study, we developed a genetic mouse model of PIK3CA-related lymphatic malformations that recapitulates human disease. Using this model, we demonstrated the efficacy of alpelisib, an approved pharmacological inhibitor of PIK3CA in oncology, in preventing lymphatic malformation occurrence, improving lymphatic anomalies, and extending survival. On the basis of these results, we treated six patients with alpelisib, including three children, displaying severe PIK3CA-related lymphatic malformations. Patients were already unsuccessfully treated with rapamycin, percutaneous sclerotherapies, and debulking surgical procedures. We assessed the volume of lymphatic malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib administration was associated with improvements in the six patients. Previously intractable vascular malformations shrank, and pain and inflammatory flares were attenuated. MRI showed a decrease of 48% in the median volume of lymphatic malformations over 6 months on alpelisib. During the study, two patients developed adverse events potentially related to alpelisib, including grade 1 mucositis and diarrhea. In conclusion, this study supports PIK3CA inhibition as a promising therapeutic strategy in patients with PIK3CA-related lymphatic anomalies.


Subject(s)
Thiazoles , Animals , Humans , Mice
4.
N Engl J Med ; 385(11): 996-1004, 2021 09 09.
Article in English | MEDLINE | ID: mdl-34496175

ABSTRACT

BACKGROUND: Cerebral cavernous malformations (CCMs) are common sporadic and inherited vascular malformations of the central nervous system. Although familial CCMs are linked to loss-of-function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3), the genetic cause of sporadic CCMs, representing 80% of cases, remains incompletely understood. METHODS: We developed two mouse models harboring mutations identified in human meningiomas with the use of the prostaglandin D2 synthase (PGDS) promoter. We performed targeted DNA sequencing of surgically resected CCMs from patients and confirmed our findings by droplet digital polymerase-chain-reaction analysis. RESULTS: We found that in mice expressing one of two common genetic drivers of meningioma - Pik3ca H1047R or AKT1 E17K - in PGDS-positive cells, a spectrum of typical CCMs develops (in 22% and 11% of the mice, respectively) instead of meningiomas, which prompted us to analyze tissue samples from sporadic CCMs from 88 patients. We detected somatic activating PIK3CA and AKT1 mutations in 39% and 1%, respectively, of lesion tissue from the patients. Only 10% of lesions harbored mutations in the CCM genes. We analyzed lesions induced by the activating mutations Pik3ca H1074R and AKT1 E17K in mice and identified the PGDS-expressing pericyte as the probable cell of origin. CONCLUSIONS: In tissue samples from sporadic CCMs, mutations in PIK3CA were represented to a greater extent than mutations in any other gene. The contribution of somatic mutations in the genes that cause familial CCMs was comparatively small. (Funded by the Fondation ARC pour la Recherche contre le Cancer and others.).


Subject(s)
Class I Phosphatidylinositol 3-Kinases/genetics , Intracranial Arteriovenous Malformations/genetics , Mutation , Proto-Oncogene Proteins c-akt/genetics , Animals , Disease Models, Animal , Female , Humans , Intracranial Arteriovenous Malformations/pathology , KRIT1 Protein/genetics , Male , Meningioma/genetics , Mice , Mice, Inbred Strains
5.
C R Biol ; 344(2): 189-201, 2021 Jul 02.
Article in English | MEDLINE | ID: mdl-34213856

ABSTRACT

This review recapitulates the recent knowledge accumulation on overgrowth syndrome related to gain of function of the phosphoinositide3 kinase (PI3K)-alpha. These disorders, known as PIK3CA related overgrowth syndromes (PROS) are caused by somatic PIK3CA mutation occurring during embryogenesis. We summarize here the currently available animal models and new treatments undergoing development.


Cette revue détaille un syndrome d'hypercroissance dysharmonieuse récemment identifié : le syndrome d'hypercroissance dysharmonieuse lié à PIK3CA. Ce syndrome est dû à une activation en mosaïque de la voie PI3K-AKT-mTOR. Une mutation activatrice du gène PIK3CA est responsable de l'activation de la voie et des manifestations cliniques associées. Dans cette revue, nous avons répertorié les modèles animaux de ces syndromes ainsi que les traitements en cours d'expérimentation.


Subject(s)
Drug Discovery , Animals , Class I Phosphatidylinositol 3-Kinases/genetics , Disease Models, Animal , Mutation
6.
Med Sci (Paris) ; 36(3): 235-242, 2020 Mar.
Article in French | MEDLINE | ID: mdl-32228842

ABSTRACT

Overgrowth syndromes are a large group of rare disorders characterized by generalized or segmental excessive growth. Segmental overgrowth syndromes are mainly due to genetic anomalies appearing during the embryogenesis and leading to mosaicism. The numbers of patients with segmental overgrowth with an identified molecular defect has dramatically increased following the recent advances in molecular genetic using next-generation sequencing approaches. This review discusses various syndromes and pathways involved in segmental overgrowth syndromes and presents actual and future therapeutic strategies.


TITLE: Les syndromes de surcroissance segmentaire et les stratégies thérapeutiques. ABSTRACT: Les syndromes de surcroissance sont un groupe de pathologies caractérisées par une croissance excessive généralisée ou segmentaire. Les syndromes de surcroissance segmentaires sont principalement dus à des anomalies génétiques apparaissant durant l'embryogenèse et aboutissant à un mosaïcisme. Le nombre de patients atteints d'un syndrome de surcroissance avec une mutation identifiée a fortement augmenté grâce à des avancées récentes en génétique moléculaire, en utilisant le séquençage de nouvelle génération (NGS). Cette revue détaille les différents syndromes de surcroissance segmentaire ainsi que les voies moléculaires impliquées et les options thérapeutiques envisageables.


Subject(s)
Growth Disorders/genetics , Growth Disorders/therapy , Mosaicism , Beckwith-Wiedemann Syndrome/genetics , Beckwith-Wiedemann Syndrome/pathology , Beckwith-Wiedemann Syndrome/therapy , Eye Diseases/genetics , Eye Diseases/pathology , Eye Diseases/therapy , Genetic Testing , Growth Disorders/diagnosis , Growth Disorders/pathology , High-Throughput Nucleotide Sequencing , Humans , Lipomatosis/genetics , Lipomatosis/pathology , Lipomatosis/therapy , Mosaicism/embryology , Mutation , Neurocutaneous Syndromes/genetics , Neurocutaneous Syndromes/pathology , Neurocutaneous Syndromes/therapy , Nevus, Sebaceous of Jadassohn/genetics , Nevus, Sebaceous of Jadassohn/pathology , Nevus, Sebaceous of Jadassohn/therapy , Phosphatidylinositol 3-Kinases/genetics , Sturge-Weber Syndrome/genetics , Sturge-Weber Syndrome/pathology , Sturge-Weber Syndrome/therapy , Syndrome
7.
Am J Kidney Dis ; 76(2): 288-291, 2020 08.
Article in English | MEDLINE | ID: mdl-31810732

ABSTRACT

Despite optimal anticoagulation and blood pressure control, patients with antiphospholipid syndrome (APS) nephropathy frequently progress to kidney failure, and recurrence after transplantation is common. The mTORC (mechanistic target of rapamycin complex) pathway was recently identified as a potential intermediate and a therapeutic target in vascular lesions associated with APS nephropathy. However, these results were derived from the retrospective analysis of a small cohort of patients receiving sirolimus after kidney transplantation. Therefore, they warranted external validation and the demonstration of the potential benefit of sirolimus in native kidney APS nephropathy. We report a patient with active APS nephropathy lesions occurring on native kidneys, in which endothelial mTORC activation was substantiated at the molecular level. Treatment with sirolimus was shown on a repeat kidney biopsy to successfully inhibit the AKT/mTORC pathway and was associated with significant improvement in kidney function and lesions of vasculopathy. Drug tolerance was excellent during the entire follow-up. This case validates and extends previous observations in kidney transplant recipients and demonstrates that endothelial activation of the AKT/mTORC pathway occurs in the damaged renal vasculature of native kidneys in APS nephropathy. These findings further support the potential of precision medicine and the use of mTORC activation as a biomarker of disease activity and as therapeutic target in patients with APS nephropathy.


Subject(s)
Antiphospholipid Syndrome/drug therapy , Immunosuppressive Agents/therapeutic use , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 2/metabolism , Renal Insufficiency, Chronic/drug therapy , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Anticoagulants/therapeutic use , Antiphospholipid Syndrome/complications , Antiphospholipid Syndrome/metabolism , Female , Humans , Microscopy, Confocal , Proto-Oncogene Proteins c-akt/metabolism , Ramipril/therapeutic use , Renal Insufficiency, Chronic/etiology , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/pathology , Ribosomal Protein S6/metabolism , Signal Transduction , Thrombotic Microangiopathies/etiology , Thrombotic Microangiopathies/metabolism , Thrombotic Microangiopathies/pathology , Treatment Outcome
9.
Nature ; 558(7711): 540-546, 2018 06.
Article in English | MEDLINE | ID: mdl-29899452

ABSTRACT

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.


Subject(s)
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/metabolism , Lipoma/drug therapy , Lipoma/enzymology , Molecular Targeted Therapy , Musculoskeletal Abnormalities/drug therapy , Musculoskeletal Abnormalities/enzymology , Nevus/drug therapy , Nevus/enzymology , Thiazoles/therapeutic use , Vascular Malformations/drug therapy , Vascular Malformations/enzymology , Adult , Animals , Child , Disease Models, Animal , Female , HeLa Cells , Heart Failure/complications , Heart Failure/drug therapy , Humans , Male , Mice , Phenotype , Scoliosis/complications , Scoliosis/drug therapy , Sirolimus/therapeutic use , Syndrome , Vascular Neoplasms/complications , Vascular Neoplasms/drug therapy
10.
Nephrol Ther ; 13 Suppl 1: S155-S156, 2017 Apr.
Article in French | MEDLINE | ID: mdl-28577738

ABSTRACT

This review presents an overview of a recently characterized spectrum of overgrowth syndrome: phosphoinositide-3 kinase (PI3K)-related overgrowth spectrum (PROS). This spectrum encompasses overgrowth syndromes associated with somatic mosaic activating PIK3CA mutations such as megalencephaly-capillary malformation (MCAP) syndrome, dysplatic megalencephaly (DMEG), congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome, hemihyperplasia-multiple lipomatosis (HHML), fibroadipose overgrowth and Klippel-Trenaunay syndrome. Mosaic gain of function mutation in PIK3CA gene leads to abnormal AKT-mTOR pathway activation and is responsible of the clinical manifestations. Here, we summarize the current knowledge on this disorder.


Subject(s)
Abnormalities, Multiple/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Growth Disorders/genetics , Mutation , Abnormalities, Multiple/diagnosis , Biomarkers/blood , Growth Disorders/diagnosis , Humans , Lipomatosis/genetics , Musculoskeletal Abnormalities/genetics , Phenotype , Syndrome , Vascular Malformations/genetics
11.
PLoS One ; 11(1): e0146962, 2016.
Article in English | MEDLINE | ID: mdl-26789121

ABSTRACT

ABCB4/MDR3, a member of the ABC superfamily, is an ATP-dependent phosphatidylcholine translocator expressed at the canalicular membrane of hepatocytes. Defects in the ABCB4 gene are associated with rare biliary diseases. It is essential to understand the mechanisms of its canalicular membrane expression in particular for the development of new therapies. The stability of several ABC transporters is regulated through their binding to PDZ (PSD95/DglA/ZO-1) domain-containing proteins. ABCB4 protein ends by the sequence glutamine-asparagine-leucine (QNL), which shows some similarity to PDZ-binding motifs. The aim of our study was to assess the potential role of the QNL motif on the surface expression of ABCB4 and to determine if PDZ domain-containing proteins are involved. We found that truncation of the QNL motif decreased the stability of ABCB4 in HepG2-transfected cells. The deleted mutant ABCB4-ΔQNL also displayed accelerated endocytosis. EBP50, a PDZ protein highly expressed in the liver, strongly colocalized and coimmunoprecipitated with ABCB4, and this interaction required the QNL motif. Down-regulation of EBP50 by siRNA or by expression of an EBP50 dominant-negative mutant caused a significant decrease in the level of ABCB4 protein expression, and in the amount of ABCB4 localized at the canalicular membrane. Interaction of ABCB4 with EBP50 through its PDZ-like motif plays a critical role in the regulation of ABCB4 expression and stability at the canalicular plasma membrane.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/biosynthesis , Cell Membrane/metabolism , Gene Expression Regulation/physiology , Hepatocytes/metabolism , Phosphoproteins/metabolism , Sodium-Hydrogen Exchangers/metabolism , ATP Binding Cassette Transporter, Subfamily B/genetics , Amino Acid Motifs , Cell Membrane/genetics , HEK293 Cells , Hep G2 Cells , Hepatocytes/cytology , Humans , PDZ Domains , Phosphoproteins/genetics , Sodium-Hydrogen Exchangers/genetics
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