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.
Authors
- Albin Sandelin (ORCID: https://orcid.org/0000-0002-7109-7378)
- Ainara Castellanos‐Rubio (ORCID: https://orcid.org/0000-0003-3192-9544)
- H. Carlo Maurer (ORCID: https://orcid.org/0000-0002-2193-6014)
- Yifan Dai (ORCID: https://orcid.org/0000-0001-7897-5228)
- Elisa Espinet (ORCID: https://orcid.org/0000-0002-0690-9878)
- Izortze Santín (ORCID: https://orcid.org/0000-0003-1651-6776)
- Peter Vilmann (ORCID: https://orcid.org/0000-0001-7889-1104)
- Luís Arnes (ORCID: https://orcid.org/0000-0002-4158-8301)
- Pia Klausen (ORCID: https://orcid.org/0000-0001-9386-9167)
- Charlotte Vestrup Rift (ORCID: https://orcid.org/0000-0002-0128-1145)
- Philip A. Seymour (ORCID: https://orcid.org/0000-0001-5782-6020)
- Anita Kurilla (ORCID: https://orcid.org/0000-0003-4829-3810)
- Marta Ballester
- Jane Hasselby
- Kristina Høj
- Katarzyna Radke
- Saynab Omar
- Aida Marisch-Delgado
- Leire Bergara-Muguruza
Institutions
- University of Copenhagen (DK)
- University of the Basque Country (ES)
- Herlev Hospital (DK)
- Copenhagen University Hospital (DK)
- Gentofte Hospital (DK)
- TUM Klinikum (DE)
- Rigshospitalet (DK)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- BioCruces Health research Institute (ES)
- Euskadiko Parke Teknologikoa (ES)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Bioef - Fundación Vasca de Innovación e Investigación Sanitarias (ES)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1016/j.celrep.2026.117176
- Primary Topic
- Developmental Biology and Gene Regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Kræftens Bekæmpelse
- Københavns Universitet
- Novo Nordisk Fonden
- HORIZON EUROPE Framework Programme