{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:41:57Z","timestamp":1785415317672,"version":"3.56.0"},"posted":{"date-parts":[[2024,1,5]]},"group-title":"Cancer Biology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T00:00:00Z","timestamp":1704412800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01 CA262526"],"award-info":[{"award-number":["R01 CA262526"]}],"id":[{"id":"https:\/\/ror.org\/02t771148","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30 CA240139"],"award-info":[{"award-number":["P30 CA240139"]}],"id":[{"id":"https:\/\/ror.org\/02t771148","id-type":"ROR","asserted-by":"publisher"}]},{"award":["22K06"],"award-info":[{"award-number":["22K06"]}],"id":[{"id":"https:\/\/ror.org\/03e1xkn26","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>BACKGROUND &amp; AIMS<\/jats:title>\n                  <jats:p>\n                    Chronic alcoholism often leads to pancreatitis, which exacerbates pancreatic damage through acinar cell injury, fibrotic inflammation and activates AKT\/mTOR\/cyclic adenosine monophosphate response element binding protein 1 (CREB) signaling axis. However, the molecular interplay between oncogenic\n                    <jats:italic>\n                      Kras\n                      <jats:sup>G12D\/+<\/jats:sup>\n                    <\/jats:italic>\n                    (\n                    <jats:italic>Kras*<\/jats:italic>\n                    ) and CREB in promoting pancreatic cancer progression under chronic inflammation remains poorly understood.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>\n                    Experimental alcoholic chronic pancreatitis (ACP) induction was established in multiple mouse models, with euthanasia during the recovery stage to evaluate tumor latency. CREB was selectively deleted (\n                    <jats:italic>\n                      Creb\n                      <jats:sup>fl\/fl<\/jats:sup>\n                    <\/jats:italic>\n                    ) in\n                    <jats:italic>\n                      Ptf1a\n                      <jats:sup>CreERTM\/+<\/jats:sup>\n                      ;LSL-Kras\n                      <jats:sup>G12D\/+<\/jats:sup>\n                    <\/jats:italic>\n                    (\n                    <jats:italic>KC<\/jats:italic>\n                    ) genetic mouse models (\n                    <jats:italic>\n                      KCC\n                      <jats:sup>-\/-<\/jats:sup>\n                    <\/jats:italic>\n                    ). Pancreata from\n                    <jats:italic>\n                      Ptf1a\n                      <jats:sup>CreERTM\/+<\/jats:sup>\n                    <\/jats:italic>\n                    ,\n                    <jats:italic>KC<\/jats:italic>\n                    , and\n                    <jats:italic>\n                      KCC\n                      <jats:sup>-\/-<\/jats:sup>\n                    <\/jats:italic>\n                    mice were analyzed using histological profiling, western blotting, phosphokinase array, and quantitative PCR. Single-cell RNA sequencing was performed in ACP-induced\n                    <jats:italic>KC<\/jats:italic>\n                    mice. Lineage tracing analysis in YFP reporter mice and acinar cell explant cultures analysis were also conducted.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    ACP induction in\n                    <jats:italic>KC<\/jats:italic>\n                    mice significantly impaired pancreas\u2019 repair mechanism. Acinar cell-derived ductal lesions demonstrated sustained CREB hyperactivation in acinar-to-ductal metaplasia (ADM)\/pancreatic intraepithelial neoplasia (PanIN) lesions associated with pancreatitis and pancreatic cancer. Persistent CREB activity reprogrammed acinar cells, and increased profibrotic inflammation. Notably, acinar specific\n                    <jats:italic>Creb<\/jats:italic>\n                    deletion in ACP induced models suppressed high grade PanIN development, restrained tumor progression, and improved acinar cell function.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>\n                    Our findings demonstrate that CREB and\n                    <jats:italic>Kras*<\/jats:italic>\n                    promote irreversible ADM, accelerating pancreatic cancer progression with ACP. Targeting CREB may present a promising strategy to mitigate inflammation-driven pancreatic tumorigenesis.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.01.05.574376","type":"posted-content","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T12:30:12Z","timestamp":1704803412000},"source":"Crossref","is-referenced-by-count":0,"title":["CREB drives acinar cells to ductal reprogramming and promotes pancreatic cancer progression in preclinical models of alcoholic 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