Early Metabolic Fate Commitment in Pancreatic Neoplastic Precursors

With a devastating 5-year survival rate of only 8%, pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers and is expected to become the second leading cause of cancer-related deaths in the USA by 2030. 1 2 Thus, the deciphering of key events driving tumour development and progression in both early and late stages of PDAC is crucial for improving diagnosis, therapy, and potentially prevention.

A hallmark of PDAC is profound metabolic reprogramming, which supports tumour cell survival in a harsh, nutrient-deprived microenvironment shaped by the disease's dense fibrotic stroma. This metabolic shift fuels cancer cell aggressiveness and contributes to the establishment of an immunosuppressive tumour microenvironment (TME).

While there has been considerable interest in elucidating addictive metabolic pathways in late-stage pancreatic tumours to develop targeted therapies, it has become evident that metabolic reprogramming also occurs in early pancreatic precursor lesions (PPLs). PDAC arises from several...