PIK3CA gain-of-function mutation in adipose tissue induces metabolic reprogramming with Warburg-like effect and severe endocrine disruption

Sci Adv. 2022 Dec 9;8(49):eade7823. doi: 10.1126/sciadv.ade7823.

Sophia Ladraa ¹ ², Lola Zerbib ¹ ², Charles Bayard ¹ ², Antoine Fraissenon ² ³ ⁴ ⁵, Quitterie Venot ¹ ², Gabriel Morin ¹ ², Alexandre P Garneau ¹ ², Pierre Isnard ¹ ⁶, Célia Chapelle ¹ ², Clément Hoguin ² ⁷, Sylvie Fraitag ⁶, Jean-Paul Duong ¹ ⁶, Laurent Guibaud ² ³, Alix Besançon ¹ ⁸, Sophie Kaltenbach ¹ ⁹, Patrick Villarese ⁹, Vahid Asnafi ¹ ² ⁹, Christine Broissand ¹⁰, Nicolas Goudin ¹¹, Michael Dussiot ¹ ¹², Ivan Nemazanyy ¹³, Thomas Viel ¹⁴, Gwennhael Autret ¹⁴, Céline Cruciani-Guglielmacci ¹ ¹⁵, Jessica Denom ¹ ¹⁵, Julie Bruneau ¹ ⁶, Bertrand Tavitian ¹ ¹⁴, Christophe Legendre ¹ ² ¹⁶, Julien Dairou ¹ ¹⁷, Jean-Marc Lacorte ¹⁸ ¹⁹, Pacifique Levy ¹⁸, Mario Pende ¹ ², Michel Polak ¹ ⁸, Guillaume Canaud ¹ ² ⁷

Affiliations

1 Université Paris Cité, Paris, France.
2 INSERM U1151, Institut Necker-Enfants Malades, Paris, France.
3 Service d'Imagerie Pédiatrique, Hôpital Femme-Mère-Enfant, HCL, Bron, France.
4 CREATIS UMR 5220, Villeurbanne 69100, France.
5 Service de Radiologie Mère-Enfant, Hôpital Nord, Saint Etienne, France.
6 Service d'Anatomie pathologique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
7 Unité de médecine translationnelle et thérapies ciblées, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
8 Service d'Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Centre des maladies endocriniennes rares de la croissance et du développement, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
9 Laboratoire d'Oncohématologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
10 Pharmacie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
11 Necker Bio-Image Analysis, INSERM US24/CNRS UMS 3633, Paris, France.
12 INSERM U1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Laboratoire d'Excellence GR-Ex, Paris, France.
13 Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Paris, France.
14 Plateforme Imageries du Vivant, Université de Paris, PARCC, INSERM, Paris, France.
15 Unité de Biologie Fonctionnelle et Adaptative, CNRS, Paris, France.
16 Service de Néphrologie, Transplantation Adultes, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
17 Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, CNRS, Paris, France.
18 Laboratoire de Biochimie Endocrinienne et Oncologique, Hôpital La Pitié Salpêtrière, AP-HP, Paris, France.
19 Sorbonne Université, Paris, France.

PMID: 36490341 DOI: 10.1126/sciadv.ade7823

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-15244

Alpelisib

99.95%, PI3Kα Inhibitor

PI3K

Cancer

Name
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