Role of PI3K-C2G in pancreatic cancer metabolism
Worldwide Cancer Research
University of Turin
Pancreatic cancer (PC) is the most lethal cancer across the world, with incidence equaling mortality. Recently, PC emerged as a metabolic outlier characterized by several metabolic dependencies, representing an unmet opportunity for the development of novel therapeutic approaches. A wealth of studies report that enhanced activation of PI3K/mTOR pathway has a critical role in the pathogenesis of PC and it is required for sustaining malignant growth and metabolism rewiring. The mTOR Complex 1 (mTORC1) is a key regulator of metabolic adaptation to nutrient availability, promoting anabolic pathways. Recently, it has been reported that PI(3,4)P2, a class II PI3K signaling product, can act as a local repressor of the mTORC1 signaling. Differently from other class II members which are ubiquitous, In particular, the PI3K-C2γ isoform is mainly expressed in the pancreatic tissue where it plays a pivotal role in cell metabolism. In human PDAC, the PIK3C2G gene is homozygous-deleted in about 7% of patients. Therefore, we decided to model PI3K-C2γ loss (PIK3C2G gene KO) in a mouse model of PC (KPC). We found that lack of PI3K-Cϒ increases tumor development and progression, strongly reducing mice mean survival rate and driving rapid progression to cancer. Biochemical analyses of PIK3C2G-deficient tumors revealed a specific hyperactivation of mTORC1 pathway, increasing metabolic alterations. To consolidate these findings, we aim at: i) assessing the oncogenic potential of PI3K-C2ϒ ii) dissecting PI3K-C2ϒ signaling pathway iii) exploiting metabolic dependencies of PI3K-C2ϒ loss iv) defining the prognostic and predictive value of PI3K-C2ϒ in PDAC. With this project, we expect to validate PI3K-C2ϒ as a novel tumor suppressor in PC and to establish a new mechanism by which PI3K-C2ϒ controls metabolic alterations induced by mTORC1 hyperactivation. Eventually, data obtained from this study will validate selective inhibition of critical metabolic pathways in PI3K-C2ϒ-deficient tumors to maximize therapeutic success.
2.1 Biological and endogenous factors