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Risk factors for PDAC, including smoking and chronic pancreatitis, trigger the unfolded protein response (UPR). Global deletion of Activating Transcription Factor 3 (ATF3), a UPR mediator, restricts preneoplastic progression in mice expressing oncogenic KRAS (KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    ). However, ATF3 is expressed in malignant and non-malignant cells suggesting it may affect multiple cell compartments in PDAC. Therefore, the goal of this study was to determine if ATF3 has epithelial-specific roles during PDAC initiation. Epithelial cells from mice expressing KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    with (\n                    <jats:italic>Ptf1a<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>creERT\/+<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>KRAS<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>G12D<\/jats:italic>\n                      \/+\n                    <\/jats:sup>\n                    ) or without ATF3 (\n                    <jats:italic>Atf3<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>Ptf1a<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>creERT\/+<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>KRAS<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>G12D\/+<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>; APK<\/jats:italic>\n                    ) were characterized before and after pancreatic injury. Additionally, mice allowing acinar-specific\n                    <jats:italic>Atf3<\/jats:italic>\n                    deletion and KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    expression (\n                    <jats:italic>A<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>acinar<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>PK<\/jats:italic>\n                    ) were compared to\n                    <jats:italic>Ptf1a<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>creERT\/+<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>KRAS<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>G12D<\/jats:italic>\n                      \/+\n                    <\/jats:sup>\n                    and\n                    <jats:italic>APK<\/jats:italic>\n                    mice following injury. RNA-seq revealed reduced oncogenic pathways in\n                    <jats:italic>APK<\/jats:italic>\n                    acinar cells consistent with reduced ADM formation in\n                    <jats:italic>APK<\/jats:italic>\n                    cultures.\n                    <jats:italic>Ptf1a<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>creERT\/+<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>KRAS<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>G12D<\/jats:italic>\n                      \/+\n                    <\/jats:sup>\n                    and\n                    <jats:italic>APK<\/jats:italic>\n                    organoids showed differential gene expression and morphology, with\n                    <jats:italic>APK<\/jats:italic>\n                    organoids exhibiting reduced viability. In vivo,\n                    <jats:italic>APK<\/jats:italic>\n                    and\n                    <jats:italic>A<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>acinar<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>PK<\/jats:italic>\n                    tissue showed restricted neoplastic progression and KRAS signaling compared to\n                    <jats:italic>Ptf1a<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>creERT\/+<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>KRAS<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>G12D<\/jats:italic>\n                      \/+\n                    <\/jats:sup>\n                    mice. This study indicates ATF3 works in a cell autonomous fashion, and its absence restricts\n                    <jats:italic>KRAS<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>G12D<\/jats:italic>\n                    <\/jats:sup>\n                    -mediated PDAC.\n                  <\/jats:p>","DOI":"10.1038\/s41420-025-02777-2","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T15:27:57Z","timestamp":1762442877000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Acinar-specific loss of activating transcription factor 3 restricts KRASG12D mediated transcriptional changes and PanIN progression"],"prefix":"10.1038","volume":"11","author":[{"given":"Mickenzie B.","family":"Martin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Mousavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Goebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenic","family":"Di Stasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alesia","family":"Mano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Glogov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liena","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Di Guglielmo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parisa","family":"Shooshtari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1245-1058","authenticated-orcid":false,"given":"Christopher L.","family":"Pin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"2777_CR1","doi-asserted-by":"publisher","first-page":"e214708","DOI":"10.1001\/jamanetworkopen.2021.4708","volume":"4","author":"L Rahib","year":"2021","unstructured":"Rahib L, Wehner MR, Matrisian LM, Nead KT. 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