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

Summary Pancreatic exocrine cell plasticity promotes cancer (PDAC). Tissue damage by inflammation (pancreatitis) is repaired by plasticity but also by a beneficial proliferative regeneration. To identify molecular drivers of proliferative turnover, we compared human samples of pancreatitis and PDAC, the latter a condition with increased plasticity. We identified PI3K activation gene signatures and, amongst those, PHGDH , encoding an enzyme responsible for serine synthesis, as differentially expressed. Caerulein or red meat-enriched diet promotes pancreatic plasticity, PI3K activation, but also increased PHGDH. Interestingly, in vitro , pharmacological or genetic PI3Kα inhibition had differential action on the level of the p27 quiescence marker depending on the level of PHGDH controlling mitochondrial activity. In vivo , genetic inactivation of PI3Kα in the pancreas led to a reduced exocrine cell plasticity but to an increase of acinar cell proliferative markers. As PI3Kα inhibitors were shown to block plasticity while maintaining pancreas mass, they may represent a preventive interception drug in patients with pancreatitis at risk of developing cancer. Summary Red meat-enriched food, a pancreatic cancer risk factor, acts as an inflammatory stress for the pancreas. Inflammation dampens beneficial exocrine cell proliferative turnover and stimulates PI3Kα-dependent precancer lesions. PI3Kα inhibitors represent a pancreatic cancer prevention drug in patient with pancreatitis.