Spatiotemporal control of SMARCA5 by a MAPK-RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from...

Acute pancreatitis-induced acinar-to-ductal metaplasia involves global chromatin remodeling and contributes to normal tissue regeneration. Oncogenic KRAS hijacks this process to promote PDAC formation. Here we show that regeneration and KRAS^G12D-driven oncogenesis can be decoupled from tissue regeneration through a chromatin remodeler, SMARCA5. We show that SMARCA5 maintains KRAS^G12D-dependent chromatin accessibility at regions specifically required for malignancy, without affecting chromatin opening that occurs during normal regeneration. Without SMARCA5, regeneration can be restored in the presence of KRAS^G12D. Mechanistically, regeneration-related or malignancy-related chromatin remodeling activities occur in a time-sensitive manner. The activity of SMARCA5 is controlled spatiotemporally by transcription factor RUNX1, which only accumulates at sufficient levels with sustained MAPK signals. We further show that inhibition of the SMARCA5-containing NoRC complex specifically inhibits the growth of PDAC organoid but not that of normal tissue derived from patients.