PI3Kα activity in PHGDH-low pancreatic epithelial cells limits tissue proliferative regeneration in cancer promoting conditions

Abstract

ObjectiveIncreased consumption of meat is an epidemiologically validated risk condition for pancreatic cancer development, but the underlying mechanisms and whether it is related to induction of epithelial cell plasticity are unknown. DesignExperimental protocol to test the influence of high consumption of meat was compared to pancreatic inflammation experimental models. To determine the molecular drivers promoting pancreatic cell plasticity, we compared transcriptomics data sets from human samples of pancreatic inflammation and pancreatic cancer (PDAC) prone to plasticity and validated in vivo, ex vivo and in vitro the main identified target. ResultsMeat-enriched diet promoted plasticity of pancreatic acinar cells, that transdifferentiated in duct-like cells, and presented PI3K activation. We identified a selective PI3K activation gene signature enriched with plasticity. In this signature, PHGDH, which encodes an enzyme responsible for amino acid serine synthesis, was differentially expressed. High level of PHGDH in acinar cells was necessary for the proliferative action of PI3K sustained by an increased maximal mitochondrial capacity and decreased cyclin-dependent inhibitor p27 level. PHGDH level was decreased in transdifferentiated acinar cells. In this context, active PI3K promoted cell plasticity but decreased the number of cycling cells. Both epithelial-restricted genetic inactivation of PI3K and full PI3K inhibition by pharmacological dosage reduced inflammation-induced tissue damage, while a pharmacological PI3K activator promoted PanIN precancer lesion development. ConclusionMeat-enriched diet promoted plasticity. Blockage of plasticity by PI3K inhibition provoked an increased rate of acinar cell proliferation that had a beneficial impact on the tissue microenvironment less prone to precancer lesion development. What is already known on this topicIt is now well accepted that inflammatory conditions predispose to pancreatic tumour development; increased consumption of red and processed meat is an epidemiologically validated risk condition, but the underlying mechanisms are unknown. What this study addsWe identify PI3K activation as a common molecular pathway activated by increased consumption of red and processed meat and by inflammatory condition to promote pancreatic plasticity and precancer lesion development. How this study might affect research, practice or policyAs we show that treatments with the clinically available PI3K inhibitor block pancreatic plasticity under inflammatory stress while maintaining pancreas mass and limiting inflammatory reaction damage, they may represent an efficient and safe preventive interception drug in patients at risk of developing pancreatic cancer. PI3K pro-cancer action is exacerbated by the loss of serine synthesis enzyme; hence, diets that alter amino acid synthesis should be tightly controlled in those patients.