TY - JOUR
T1 - Multifaceted role for p53 in pancreatic cancer suppression
AU - Mello, Stephano S.
AU - Flowers, Brittany M.
AU - Mazur, Pawel K.
AU - Lee, James J.
AU - Müller, Fabian
AU - Denny, Sarah K.
AU - Ferreira, Sofia
AU - Hanson, Kathryn
AU - Kim, Seung K.
AU - Greenleaf, William J.
AU - Wood, Laura D.
AU - Attardi, Laura D.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Julien Sage for critical reading of this manuscript and Patrick Neuhoefer for valuable input.This work was supported by NIH, through R21 CA169673, R01 CA140875, and R35 CA197591 grants to L.D.A.
Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS.
PY - 2023/3/7
Y1 - 2023/3/7
N2 - 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.
AB - 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.
KW - ADM
KW - PanIN
KW - p53
KW - pancreatic cancer
KW - pancreatitis
UR - http://www.scopus.com/inward/record.url?scp=85148971299&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85148971299&partnerID=8YFLogxK
U2 - 10.1073/pnas.2211937120
DO - 10.1073/pnas.2211937120
M3 - Article
C2 - 36848578
AN - SCOPUS:85148971299
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
M1 - e2211937120
ER -