Investigating the metabolic consequences resulting from the oncogenic activation of the PI3K-AKT pathway

© 2020 Sabrina CaiazzoThe phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly activated pathways in a variety of cancers and it has recently been highlighted as one of the primary modulators of cell metabolism. This has opened promises and challenges for the development of therapeutic strategies to target metabolism in cancer cells harbouring mutations in the PI3K pathway. Through an inducible “exon switch” approach, our laboratory has previously generated mice ubiquitously expressing a mutation in Pik3ca, the gene coding for the subunit p110alpha of PI3K. By using this mouse model (UbCreERPik3caH1047R) our laboratory has shown that mutations in the PI3K pathway lead to dramatic severe defects in glucose homeostasis resulting in hypoglycaemia and hypoinsulinemia. In this thesis the causes responsible for the metabolic dysfunction observed in these mutant mice are investigated. This thesis provides evidence that mutations in the PI3K pathway lead to increased glucose uptake by the tissues, inhibition of hepatic gluconeogenesis and inhibition of insulin release from the pancreas. Previous studies performed on the UbCreERPik3caH1047R mouse model have also shown increased body weight and organomegaly. This thesis demonstrates that the increase in body weight, resulting from the activation of the Pik3caH1047R mutation was not associated with adiposity. On the contrary, mutations in the PI3K pathway determine loss of body fat and increased lipolysis in the adipose tissue of mice, whilst the tissue growth is associated to hypertrophy or hyperplasia. Furthermore, oncogenic activation of the Pik3caH1047R mutation in vivo leads to alteration of the respiratory exchange rate and energy expenditure of the mice and stimulates browning of the adipose tissue. This thesis also shows that activation of the PI3K pathway alters the expression of genes and proteins involved in metabolic pathways, and that these alterations are organ-specific, therefore opening promises for customising treatments to individual patients