Meat enriched-diet and inflammation promote PI3Kα-dependent pancreatic cell plasticity that limit tissue regeneration

Objective Increased 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. Design Experimental 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. Results Meat-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 PI3Kα 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 PI3Kα promoted cell plasticity but decreased the number of cycling cells. Both epithelial-restricted genetic inactivation of PI3Kα and full PI3Kα inhibition by pharmacological dosage reduced inflammation-induced tissue damage, while a pharmacological PI3Kα activator promoted PanIN precancer lesion development. Conclusion Meat-enriched diet promoted plasticity. Blockage of plasticity by PI3Kα 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 topic It 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 adds We 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 policy As we show that treatments with the clinically available PI3Kα 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. ### Competing Interest Statement F Pierre, F Gueraud have some research projects from their academic research teams that have been co-financed by the processed meat sector. The other authors declare no conflict of interest.