Multifaceted Role for p53 in Pancreatic Cancer Suppression

Authors

Stephano S Mello
Brittany M Flowers
Pawel K Mazur
James J Lee
Fabian Müller
Sarah K Denny
Sofia Ferreira
Kathryn Hanson
Seung K Kim
William J Greenleaf
Laura D Wood
Laura D Attardi

Publication Date

3-7-2023

Journal

Proceedings of the National Academy of Sciences of the United States of America

Abstract

The vast majority of human pancreatic ductal adenocarcinomas (PDACs) harbor TP53 mutations, underscoring p53's critical role in PDAC suppression. PDAC can arise when pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), giving rise to premalignant pancreatic intraepithelial neoplasias (PanINs), which finally progress to PDAC. 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. Using both inflammation-induced and KRASG12D-driven PDAC models, we find that p5353,54 both limits ADM accumulation and suppresses PanIN cell proliferation and does so more effectively than wild-type p53. Moreover, p5353,54 suppresses KRAS signaling in PanINs and limits effects on the extracellular matrix (ECM) remodeling. While p5353,54 has highlighted these functions, we find that pancreata in wild-type p53 mice similarly show less ADM, as well as reduced PanIN cell proliferation, KRAS signaling, and ECM remodeling relative to Trp53-null mice. 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.

Keywords

Humans, Animals, Mice, Proto-Oncogene Proteins p21(ras), Tumor Suppressor Protein p53, Pancreatic Neoplasms, Pancreas, Precancerous Conditions, Metaplasia, Mice, Knockout, p53, pancreatitis, pancreatic cancer, ADM, PanIN

Comments

Supplementary Materials

Data Availability Statement

PMID: 36848578