PIK3CA gain-of-function mutation in adipose tissue induces metabolic reprogramming with Warburg-like effect and severe endocrine disruption
Sophia Ladraa, Lola Zerbib, Charles Bayard, Antoine Fraissenon, Quitterie Venot, G Morin, Alexandre P. Garneau, Pierre Isnard, Célia Chapelle, Clément Hoguin, Sylvie Fraitag, Jean–Paul Duong Van Huyen, Laurent Guibaud, Alix Besançon, Sophie Kaltenbach, Patrick Villarèse, Vahid Asnafi, Christine Broissand, Nicolas Goudin, Michaël Dussiot, Ivan Nemazanyy, Thomas Viel, Gwennhaël Autret, Céline Cruciani‐Guglielmacci, Jessica Denom, Julie Bruneau, Bertrand Tavitian, Christophe Legendre, Julien Dairou, Jean‐Marc Lacorte, Pacifique Levy, Mario Pende, Michel Polak, Guillaume Canaud
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.