PIK3CA gain-of-function mutation in adipose tissue induces metabolic reprogramming with Warburg-like effect and severe endocrine disruption-Reference-Cited by-同舟云学术

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

Published:2022-12-09 Issue:49 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Ladraa Sophia¹²^ORCID,Zerbib Lola¹²,Bayard Charles¹²,Fraissenon Antoine²³⁴⁵^ORCID,Venot Quitterie¹²,Morin Gabriel¹²^ORCID,Garneau Alexandre P.¹²^ORCID,Isnard Pierre¹⁶,Chapelle Célia¹²,Hoguin Clément²⁷,Fraitag Sylvie⁶,Duong Jean-Paul¹⁶^ORCID,Guibaud Laurent²³,Besançon Alix¹⁸,Kaltenbach Sophie¹⁹,Villarese Patrick⁹^ORCID,Asnafi Vahid¹²⁹,Broissand Christine¹⁰,Goudin Nicolas¹¹^ORCID,Dussiot Michael¹¹²,Nemazanyy Ivan¹³^ORCID,Viel Thomas¹⁴^ORCID,Autret Gwennhael¹⁴^ORCID,Cruciani-Guglielmacci Céline¹¹⁵^ORCID,Denom Jessica¹¹⁵^ORCID,Bruneau Julie¹⁶,Tavitian Bertrand¹¹⁴^ORCID,Legendre Christophe¹²¹⁶,Dairou Julien¹¹⁷,Lacorte Jean-Marc¹⁸¹⁹^ORCID,Levy Pacifique¹⁸,Pende Mario¹²,Polak Michel¹⁸,Canaud Guillaume¹²⁷^ORCID

Affiliation:

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.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference51 articles.

2. Somatic Mosaic Activating Mutations in PIK3CA Cause CLOVES Syndrome

3. PI3K isoforms in cell signalling and vesicle trafficking

4. Phosphoinositide 3-kinase-dependent activation of Rac

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