PI3Kα signaling controls the balance between tissue regeneration and precancer lesion formation via PHGDH expression in pancreatic inflammation.
Résumé
Purpose: Molecular events underlying risk factors for pancreatic cancer are insufficiently understood. Because pancreatic acinar-to-ductal transdifferentiation represents one of the key features occurring at initiation of both pancreatic cancer and its risk condition pancreatitis, we searched for common molecular mechanisms explaining chronic pancreatitis susceptibility to pancreatic cancer development. Experimental Design: PI3K signal activation was assessed in Human pancreatitis samples using immunohistochemistry directed against a phosphorylated downstream target of PI3K, Akt. To model the initiation of chronic pancreatitis, repeated stress was induced in wild type and pancreatic PI3Kα activity-deficient mice (genetic or pharmacological inactivation) by 7 h intraperitoneal injections of caerulein every 3 days for 1 week to three weeks in the context of WT or oncogenic Kras. Results: Upon modeling pancreatic cancer initiation in inflammatory conditions by mutating Kras in pdx1 lineage, pharmacological inactivation of PI3Kα performed after the induction of preneoplastic lesions renormalized the pancreas. In human chronic pancreatitis, situation at risk of developing PDAC, Akt signal was found in acinar-to-ductal metaplastic (ADM) structures and was not activated in other cellular subtypes. Upon modeling the onset of chronic pancreatitis, PI3Kα activity-deficient pancreas showed a decrease of inflammatory fibroreaction. The genetic inactivation of PI3Kα decreased the number of CK19-positive ductlike cells, maintained the expression of acinar markers, and prevented the formation of ADM structures, at the origin of pancreatic cancer. Strikingly, this was associated with a dual increase of both apoptotic and proliferative index in regenerating pancreatic exocrine parenchyma. Comparison of a PI3Kα gene signature in chronic pancreatitis to PDAC patients highlighted PHGDH as a potential differential downstream target. In vitro, pharmacological inactivation of PI3Kα controlled PHGDH expression. Conclusion: Activation of PI3K/Akt pathway found in chronic pancreatitis patients enhances tissue damage irreversibility and contributes to the mild increased risk of pancreatic cancer observed in this pathological context.