{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:02:57Z","timestamp":1791558177598,"version":"4.3.4"},"reference-count":64,"publisher":"National Academy of Sciences","issue":"10","license":[{"start":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T00:00:00Z","timestamp":1677456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R21 CA169673"],"award-info":[{"award-number":["R21 CA169673"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01 CA140875"],"award-info":[{"award-number":["R01 CA140875"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R35 CA197591"],"award-info":[{"award-number":["R35 CA197591"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,3,7]]},"abstract":"<jats:p>\n                    The vast majority of human pancreatic ductal adenocarcinomas (PDACs) harbor\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations, underscoring p53\u2019s 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\n                    <jats:italic>TP53<\/jats:italic>\n                    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\u2014p53\n                    <jats:sup>53,54<\/jats:sup>\n                    \u2014which 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 KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    -driven PDAC models, we find that p53\n                    <jats:sup>53,54<\/jats:sup>\n                    both limits ADM accumulation and suppresses PanIN cell proliferation and does so more effectively than wild-type p53. Moreover, p53\n                    <jats:sup>53,54<\/jats:sup>\n                    suppresses KRAS signaling in PanINs and limits effects on the extracellular matrix (ECM) remodeling. While p53\n                    <jats:sup>53,54<\/jats:sup>\n                    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\n                    <jats:italic>Trp53<\/jats:italic>\n                    -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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2211937120","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T15:17:27Z","timestamp":1677511047000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":58,"title":["Multifaceted role for p53 in pancreatic cancer suppression"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2484-086X","authenticated-orcid":false,"given":"Stephano S.","family":"Mello","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1030-306X","authenticated-orcid":false,"given":"Brittany M.","family":"Flowers","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5820-8344","authenticated-orcid":false,"given":"Pawel K.","family":"Mazur","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Calico Life Sciences LLC, South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5809-2321","authenticated-orcid":false,"given":"Fabian","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Integrative Cellular Biology and Bioinformatics, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah K.","family":"Denny","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9535-2161","authenticated-orcid":false,"given":"Sofia","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3528-0797","authenticated-orcid":false,"given":"Kathryn","family":"Hanson","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung K.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1409-3095","authenticated-orcid":false,"given":"William J.","family":"Greenleaf","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura D.","family":"Wood","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1782-9045","authenticated-orcid":false,"given":"Laura D.","family":"Attardi","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 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