Abstract
Loss-of-function mutations in the TP53 gene are the most frequent genetic events in human malignancies. However, the extent to which missense TP53 mutations confer oncogenic gain-of-function (GOF) properties remains incompletely understood. Using genetically defined pancreatic cancer organoid models, we demonstrated that mutant p53 provides a selective growth advantage under acute environmental stress and drives molecular transition toward a basal-like state. Transcriptomic analyses showed that under stress conditions, organoids expressing mutant p53 adopted a basal-like gene expression program, a characteristic of a poor prognosis subtype of pancreatic cancer. Furthermore, the molecular subtype was reversed to the classical subtype once it returned to normal growth conditions, suggesting that transcriptional plasticity arises from acute changes in the tissue microenvironment. Given these context-dependent oncogenic properties, our findings suggest that targeting mutant p53 may be a promising therapeutic strategy for pancreatic cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s00018-025-05945-w.