Journal
SCIENCE ADVANCES
Volume 8, Issue 49, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.ade7823
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Funding
- European Research Council [101000948]
- Agence Nationale de la Recherche-Programme d'Investissements d'Avenir [ANR-18-RHUS-005]
- Agence Nationale de la Recherche-Programme de Recherche Collaborative [19-CE14-0030-01]
- CLOVES Syndrome Community (West Kennebunk, USA)
- Association Syndrome de CLOVES (Nantes, France)
- Fondation d'entreprise IRCEM (Roubaix, France)
- Fonds de dotation Emmanuel BOUSSARD (Paris, France)
- Fondation DAY SOLVAY (Paris, France)
- Fondation TOURRE (Paris, France)
- Fondation BETTENCOURT SCHUELLER (Paris, France)
- Fondation Simone et Cino DEL DUCA (Paris, France)
- Fondation Line RENAUD-Loulou GASTE (Paris, France)
- Fondation Schlumberger pour l'Education et la Recherche (Paris, France)
- Association Robert Debre pour la Recherche Medicale
- WonderFIL smiles-A Facial Infiltrating Lipomatosis community (Norway)
- INSERM
- Assistance Publique Hopitaux de Paris, l'Universite Paris Cite and Fondation pour la Recherche Medicale [FDM202006011222]
- Banting Postdoctoral Fellowship [472149]
- France Life Imaging [ANR-11-INBS-0006]
- Infrastructures BiologieSante (IBISA)
- European Research Council (ERC) [101000948] Funding Source: European Research Council (ERC)
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This study establishes a mouse model that mimics PIK3CA-related adipose tissue overgrowth and demonstrates the metabolic anomalies and endocrine disruption caused by PIK3CA mutations. The results also suggest the potential efficacy of alpelisib in preventing and improving PIK3CA-related adipose tissue overgrowth.
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 lowcirculating levels. Mouse phenotypewas 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.
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