Regulatory elements of pancreas development license the initiation of pancreatic ductal adenocarcinoma.
Cellular plasticity and transitional cellular states are crucial for tissue regeneration across multiple organs. In the pancreas, oncogenic Kras hijacks this program, acting on tissue-specific enhancers to prevent the resolution of acinar-to-ductal metaplasia (ADM) and lock regeneration into a pro-inflammatory state that progresses to cancer. Enhancer transcription, an early event during cellular state transitions, can generate stable enhancer-associated long noncoding RNAs (lncRNAs) positioned near key transcription factors and chromatin contact boundaries, often enriched for disease-associated variants. While enhancer-associated lncRNAs have been implicated in transcriptional regulation and genome organization, their role in pancreas regeneration and cancer initiation has remained unexplored. In this study, we identified epithelial long noncoding RNAs (lncRNAs) and their target genes in PDAC precursor lesion formation. We demonstrate that LINC00673, expressed from a Sox9-associated super-enhancer during pancreatic development, is reactivated in PDAC. Conditional deletion of LINC00673 in the murine pancreatic epithelium accelerates resolution of ADM and significantly impairs PDAC initiation. Furthermore, we highlight a previously unrecognized role of transcribed super-enhancers in facilitating long-range gene regulation and genome organization during pancreatic cancer initiation. Our study identifies a critical function of LINC00673 in regulating both cell-autonomous and non-cell-autonomous processes during pancreas regeneration and Kras-driven cancer initiation. These findings reveal a novel regulatory layer linking developmental enhancer activity to pancreatic disease progression and highlight new therapeutic opportunities targeting regenerative programs at the earliest stages of neoplastic transformation. Overall design: RNA sequencing was performed on pancreas of E15.5 embryos of WT (mLINC00673fl/fl) and conditional deletion (Pdx1Cre, mLINC00673fl/fl) of the mouse ortholog of LINC00673 (2610035D17Rik). Each replicate represents an independent animal.