Regulatory elements in the Sox9 locus license the initiation of pancreatic ductal adenocarcinoma.

Cellular plasticity enables tissue regeneration but can be hijacked by oncogenic programs. In the pancreas, Kras acts on tissue-specific enhancers to lock regeneration into a pro-inflammatory state that drives cancer initiation. Enhancer transcription, an early event during cell state transitions, generates long noncoding RNAs (lncRNAs) that influence transcription and genome organization, yet their roles in pancreatic regeneration remain unclear. We profiled epithelial lncRNAs and their targets during pancreatic ductal adenocarcinoma (PDAC) precursor formation, focusing on those transcribed from enhancers near cell identity regulators. LINC00673, expressed from a Sox9-associated super-enhancer during development, is reactivated in PDAC. Conditional deletion of LINC00673 accelerates acinar-to-ductal metaplasia resolution and impairs PDAC initiation. Moreover, LINC00673 harbors a variant associated with PDAC risk. In addition, our data are consistent with a contribution of transcribed super-enhancers to long-range gene regulation during pancreatic cancer initiation. These findings reveal a regulatory layer linking developmental enhancer activity, cellular plasticity, and pancreatic disease progression.