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How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement novel Ptf1a-TdTomato mice and multiple KRAS mutants across an array of genetic, pharmacologic, and inflammatory perturbations\n                  <jats:bold>\n                    <jats:italic>in vivo<\/jats:italic>\n                  <\/jats:bold>\n                  . Whereas KRAS\n                  <jats:sup>G12D<\/jats:sup>\n                  co-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRAS\n                  <jats:sup>G12R\/V<\/jats:sup>\n                  can initiate but not sustain dedifferentiated and neoplastic transcriptional and epigenetic programs. We find the KRAS\n                  <jats:sup>G12R\/V<\/jats:sup>\n                  defects consist of a failure to invoke robust EGFR signaling and activate Rac1\/Vav1, with constitutive Akt activation\n                  <jats:bold>\n                    <jats:italic>in vivo<\/jats:italic>\n                  <\/jats:bold>\n                  sufficient to rescue the tumorigenic potential of KRAS\n                  <jats:sup>G12R<\/jats:sup>\n                  . As the marked heterogeneity among KRAS variants begins early in tumorigenesis, these data are crucial to understanding mutation-specific oncogenic trajectories and directing the implementation of\n                  <jats:bold>\n                    <jats:italic>KRAS<\/jats:italic>\n                  <\/jats:bold>\n                  -directed therapeutics.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>SIGNIFICANCE<\/jats:title>\n                  <jats:p>\n                    Defining how\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutants drive distinct outcomes in human pancreatic cancer is critical for developing allele-specific therapeutic approaches. This study unveils a hierarchy among KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    , KRAS\n                    <jats:sup>G12V<\/jats:sup>\n                    , and KRAS\n                    <jats:sup>G12R<\/jats:sup>\n                    to drive tumor initiation, owing to heterogeneous activation of EGFR, PI3K\/AKT, and RAC1 signaling, thus revealing mutation-specific evolutionary paths in pancreatic tumorigenesis.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.28.656689","type":"posted-content","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T14:10:15Z","timestamp":1748787015000},"source":"Crossref","is-referenced-by-count":2,"title":["Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis"],"prefix":"10.64898","author":[{"given":"Adrien","family":"Grimont","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David 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