Regulatory elements of pancreas development license the initiation of pancreatic ductal adenocarcinoma
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Le résumé fourni par la source
Abstract 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 investigated the expression of epithelial long noncoding RNAs (lncRNAs) and their target genes in PDAC precursor lesion formation. We focus on lncRNAs transcribed from enhancer elements near cell identity transcription factors. 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. Notably, LINC00673 harbors a variant associated with risk of developing PDAC. 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. Furthermore, we highlight a previously unrecognized role of transcribed super-enhancers in facilitating long-range gene regulation during pancreatic cancer initiation. These findings reveal a novel regulatory layer linking developmental enhancer activity, cellular plasticity and pancreatic disease progression. Teaser Long noncoding RNAs from developmental enhancers play a role in long-range gene regulation with crucial biological impacts in development and cancer. Grant support This project has been supported by the Danish Cancer Society (R302-A17481). LA is supported by core funding of the Biotech Research and Innovation Center, the Danish Cancer Society (R302-A17481, R322-A17.350), The Novo Nordisk Foundation (NNF21OC0070884) and The Innovation Fund (Eurostars 2807). The Novo Nordisk Foundation Center for Stem Cell Biology was supported by Novo Nordisk Foundation grants NNF17CC0027852.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Regulatory elements of pancreas development license the initiation of pancreatic ductal adenocarcinoma
- Date Crossref
- 08/06/2025
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Copenhagen Biotech Research and Innovation Centre (BRIC) pays non établi dans la noticeUniversité ou école supérieure
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TUM Klinikum pays non établi dans la noticeÉtablissement de santé
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Technical University of Munich pays non établi dans la noticeUniversité ou école supérieure
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Institut d'Investigació Biomédica de Bellvitge Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell) pays non établi dans la noticeStructure de recherche
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Universitat de Barcelona pays non établi dans la noticeUniversité ou école supérieure
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Copenhagen University Hospital Department of Pathology pays non établi dans la noticeÉtablissement de santé
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Rigshospitalet pays non établi dans la noticeÉtablissement de santé
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Herlev Hospital pays non établi dans la noticeÉtablissement de santé
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Gentofte Hospital pays non établi dans la noticeÉtablissement de santé
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School of Medicine Department of Internal Medicine II pays non établi dans la noticeUniversité ou école supérieure
Biotech Research and Innovation Centre (BRIC) — University of Copenhagen, TUM Klinikum et Technical University of Munich, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.