Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis

Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutantKrasin the formation of pancreatic cancer (PDAC). 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 perturbationsin vivo. Whereas KRAS^G12Dco-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRAS^G12R/Vcan initiate but not sustain dedifferentiated and neoplastic transcriptional and epigenetic programs. We find the KRAS^G12R/Vdefects consist of a failure to invoke robust EGFR signaling and activate Rac1/Vav1, with constitutive Akt activationin vivosufficient to rescue the tumorigenic potential of KRAS^G12R. 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 ofKRAS-directed therapeutics.