The role of p53 in pancreatic cancer suppression
The occurrence of TP53 mutations in late-stage PanINs has led to the idea that p53 acts to suppress malignant transformation of PanINs to PDAC. However, the cellular basis for p53 action during PDAC development has not been explored in detail. Here, we leverage a hyperactive p53 variant – p5353,54 – which we previously showed is a more robust PDAC suppressor than wild-type p53, to elucidate how p53 acts at the cellular level to dampen PDAC development. We find that p5353,54 both limits ADM accumulation and suppresses PanIN cell proliferation and does so more effectively than wild-type p53. We find further that p53 enhances chromatin accessibility at sites controlled by acinar cell identity transcription factors. These findings reveal that p53 acts at multiple stages to suppress PDAC, both by limiting metaplastic transformation of acini and by dampening KRAS signaling in PanINs, thus providing key new understanding of p53 function in PDAC. Overall design: The pancreas from KrasLSL-G12D/+;Ptf1a-Cre;Trp53+/+ (n=3) and KrasLSL-G12D/+;Ptf1a-Cre;Trp53fl/fl (n=4) mice at ~3 and 1 months of age, respectively, were dissociated, and acinar cells were sorted using a surface marker for acinar cell identity (CD49F), as well as markers to exclude ductal-like cells (CD133), erythroid (TER-119) and immune cells (CD45).