5 PIK3c2G loss promotes pancreatic cancer through MTOR regulation and metabolic rewiring

Abstract

IntroductionPancreatic Ductal Adenocarcinoma (PDAC) is the most lethal cancer across the world, with incidence equaling mortality. The lack of progress in early diagnosis and effective therapies are the main reasons why improvements in PDAC death rates have been so scarce. A wealth of studies have identified mutant KRAS as the driver event for PDAC initiation, maintenance and progression, activating a plethora of downstream effector pathways. However, our understanding for critical Ras effectors is still very limited. The PI3K/AKT axis is uniformly activated in KRAS-driven PDAC, impacting on tumour growth and metabolism. Whereas the majority of efforts have so far focused on class I PI3K, increasing evidence is pointing to the importance of class II enzymes in cell proliferation and survival. In particular, PI3K-C2γ, differently from other class II members, is mainly expressed in the pancreatic and survival. In particular, PI3K-C2γ, differently from other class II members, is mainly expressed in the pancreatic tissue where it plays a pivotal role in insulin signalling.Material and methodsMouse model of PDAC (K-RASG12D/Trp53R172H/CrePdx1) was crossed with mouse strain lacking PI3K-C2γ expression. Mice were weekly followed for survival, tumour appearance and growth. Tumour lesions were evaluated by histopathological and immunofluorescence analysis. Functional in vitro and in vivo experiments were performed.Results and discussionsWe modelled PI3K-C2γ loss in PDAC by targeting PIK3C2G gene in a mouse model of pancreatic cancer (KPC) and found that its deletion both initiates and promotes pancreatic tumour development. Loss of PI3K-C2γ in KPC mice strongly reduces mice mean survival rate (18 weeks vs 36 weeks) and drives rapid progression to PDAC. Low PI3K-C2γ expression was significantly associated with poor survival and increased resistance to chemotherapeutic agents in pancreatic tumours. We observed that PI3K-C2γ can control autophagy in tumour cells through the mTORC1 pathway. In addition, we showed that PI3K-C2γ promotes the metabolic rewiring of PDAC, regulating several prominent metabolic factors, including glycolytic enzymes (PKM2, HK2 and LDH), glucose (GLUT1) and monocarboxylate(MCT4) transporters. Furthermore, pharmacological inhibition of autophagy in PIK3C2G-/- KPC leads to tumour regressionConclusionOverall, these findings establish PI3K-C2γ as a PDAC tumour suppressor and suggest that the metabolic phenotype of PI3K-C2γ-deficient tumours can be exploited by specific therapeutic strategies.