{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:15:33Z","timestamp":1785417333303,"version":"3.56.0"},"posted":{"date-parts":[[2025,12,1]]},"group-title":"Cancer Biology","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30CA036727"],"award-info":[{"award-number":["P30CA036727"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["CA277161-01A1"],"award-info":[{"award-number":["CA277161-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30CA016672"],"award-info":[{"award-number":["P30CA016672"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R21CA249924"],"award-info":[{"award-number":["R21CA249924"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1R37CA237384"],"award-info":[{"award-number":["1R37CA237384"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 CA282786"],"award-info":[{"award-number":["R01 CA282786"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["HT94252310665"],"award-info":[{"award-number":["HT94252310665"]}],"id":[{"id":"https:\/\/ror.org\/0447fe631","id-type":"ROR","asserted-by":"publisher"}]},{"award":["HT94252410921"],"award-info":[{"award-number":["HT94252410921"]}],"id":[{"id":"https:\/\/ror.org\/0447fe631","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RP200173"],"award-info":[{"award-number":["RP200173"]}],"id":[{"id":"https:\/\/ror.org\/0003xa228","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Dietary macronutrient composition has emerged as a key modulator of pancreatic tumorigenesis, yet the impact of lipid-rich diets, particularly ketogenic diets (KD) on the earliest stages of pancreatic cancer development remains unclear. To investigate how dietary lipids shape the initiation and progression of Kras-driven neoplasia, we examined the effects of low-fat diet (LFD), high-fat diet (HFD), and KD in the\n                  <jats:italic>\n                    Ptf1a\n                    <jats:sup>CreERT2<\/jats:sup>\n                    ;Kras\n                    <jats:sup>G12V<\/jats:sup>\n                    (Acinar\n                    <jats:sup>KrasG12V<\/jats:sup>\n                    )\n                  <\/jats:italic>\n                  mouse model. KD-fed mice showed the shortest survival (median 26 \u00b1 7 days) compared with SD (87 \u00b1 29; p = 0.02) and LFD (57 \u00b1 27; p = 0.02), while HFD-fed mice also exhibited reduced survival relative to SD (35 \u00b1 25; p = 0.05). KD feeding induced severe glucose intolerance and elevated circulating \u03b2-hydroxybutyrate levels. Histologically, KD-fed\n                  <jats:italic>\n                    Acinar\n                    <jats:sup>KrasG12V<\/jats:sup>\n                  <\/jats:italic>\n                  mice developed invasive, sarcomatoid-like pancreatic ductal adenocarcinoma (PDAC), while HFD-fed mice showed increased poorly differentiated PDAC; in both groups these aggressive tumors were associated with extensive fibrosis and increased stromal CD39 expression relative to tumor compartments. Proteomic analysis demonstrated activation of PI3K\u2013Akt\u2013mTOR and EGFR signaling in KD and HFD-fed\n                  <jats:italic>\n                    Acinar\n                    <jats:sup>KrasG12V<\/jats:sup>\n                  <\/jats:italic>\n                  mice. Serum cytokines\/chemokines profiling revealed pro-inflammatory and pro-angiogenic milieu in KD-fed\n                  <jats:italic>\n                    Acinar\n                    <jats:sup>KrasG12V<\/jats:sup>\n                  <\/jats:italic>\n                  mice. Collectively, these results show that dietary lipid enrichment prior to oncogenic Kras activation may accelerate early pancreatic neoplasia and foster a microenvironment conducive to tumor progression. These findings underscore the need for careful consideration of KD use in individuals at elevated risk for pancreatic cancer.\n                <\/jats:p>","DOI":"10.1101\/2025.11.26.690783","type":"posted-content","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T23:00:13Z","timestamp":1764630013000},"source":"Crossref","is-referenced-by-count":0,"title":["Dietary Fat Content Influences PanIN Progression and Pancreatic Cancer Development in Mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7984-3294","authenticated-orcid":false,"given":"Urvinder Kaur","family":"Sardarni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0731-2122","authenticated-orcid":false,"given":"Erika Y.","family":"Faraoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa M.","family":"Waller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2347-4431","authenticated-orcid":false,"given":"Lincoln N.","family":"Strickland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4272-6654","authenticated-orcid":false,"given":"Baylee","family":"O\u2019Brien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4590-7381","authenticated-orcid":false,"given":"Jesse L.","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9915-0943","authenticated-orcid":false,"given":"Florencia","family":"McAllister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4750-106X","authenticated-orcid":false,"given":"Jennifer M.","family":"Bailey-Lundberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025120317402726000_2025.11.26.690783v1.1","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-13-0065"},{"key":"2025120317402726000_2025.11.26.690783v1.2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.08.018"},{"key":"2025120317402726000_2025.11.26.690783v1.3","doi-asserted-by":"crossref","unstructured":"Zhu L , Ji J , Ma J , Wang D , Liu M , Du JX , et al. 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