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Analysis of institutional authors

Kalisz MAuthorBernardo EAuthorBeucher AAuthorMaestro, Miguel AngelAuthorGrau VAuthorVaquero EAuthorFerrer JCorresponding Author

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May 15, 2020
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Article

HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer

Publicated to: Embo Journal. 39 (9): e102808- - 2020-05-04 39(9), DOI: 10.15252/embj.2019102808

Authors: Kalisz, M; Bernardo, E; Beucher, A; Maestro, MA; del Pozo, N; Millan, I; Haeberle, L; Schlensog, M; Safi, SA; Knoefel, WT; Grau, V; de Vas, M; Shpargel, KB; Vaquero, E; Magnuson, T; Ortega, S; Esposito, I; Real, FX; Ferrer, J

Affiliations

Barcelona Inst Sci & Technol BIST, Ctr Genom Regulat CRG, Bioinformat & Genom Program, Barcelona, Spain - Author
Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. - Author
Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Barcelona, Spain. - Author
CiberEHD, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, IDIBAPS, Barcelona, Spain. - Author
CIBERONC, Madrid, Spain - Author
CIBERONC, Madrid, Spain. - Author
Ctr Invest Biomed Red Diabet & Enfermedades Metab, Barcelona, Spain - Author
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. - Author
Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. - Author
Department of Surgery, Heinrich-Heine University and University Hospital of Düsseldorf, Düsseldorf, Germany. - Author
Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain. - Author
Heinrich Heine Univ, Dept Surg, Dusseldorf, Germany - Author
Heinrich Heine Univ, Inst Pathol, Dusseldorf, Germany - Author
Hosp Clin Barcelona, Inst Malalties Digest & Metabol, IDIBAPS, CiberEHD, Barcelona, Spain - Author
Imperial Coll London, Dept Med, Sect Epigen & Dis, London, England - Author
Institute of Pathology, Heinrich-Heine University and University Hospital of Düsseldorf, Düsseldorf, Germany. - Author
Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London, UK. - Author
Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain - Author
Spanish Natl Canc Res Ctr CNIO, Transgen Unit, Madrid, Spain - Author
Transgenics Unit, Spanish National Cancer Research Centre-CNIO, Madrid, Spain. - Author
Univ Hosp Dusseldorf, Dusseldorf, Germany - Author
Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA - Author
Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA - Author
Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain - Author
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Abstract

Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding Lysine-specific demethylase 6A, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutant transcriptomes phenocopy those of Kdm6a mutations, and both defects synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic, and biochemical studies to show that HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. We also identify a subset of non-classical PDAC samples that exhibit the HNF1A/KDM6A-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A deficiency promotes PDAC. They also connect the tumor-suppressive role of KDM6A deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.© 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Keywords

Acinar cellsAnimalsBindingCarcinoma, pancreatic ductalChip-seqEpigenesis, geneticExpressionGeneGene expression regulation, neoplasticGene regulatory networksHepatocyte nuclear factor 1-alphaHistone demethylase utxHistone demethylasesHnf1aHnf1a protein, humanHumansKdm6aKdm6a protein, humanMiceMutationMutationsNon-classical pdacOrgan specificityPancreasPancreas differentiationPancreatic neoplasmsSet enrichment analysisSubtypesTumorWeb server

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Embo Journal due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 22/295, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biochemistry & Molecular Biology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 2.15. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 13, 2025)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 1.98 (source consulted: FECYT Mar 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-12-16, the following number of citations:

  • WoS: 58
  • Scopus: 46
  • Europe PMC: 38

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-12-16:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 75.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 75 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 21.
  • The number of mentions on the social network X (formerly Twitter): 38 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Germany; United Kingdom; United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Bladé Creixenti, Joan) and Last Author (Ferrer Marrades, Jorge Pedro).

the author responsible for correspondence tasks has been Ferrer Marrades, Jorge Pedro.

Awards linked to the item

Generalitat de Catalunya We thank I. Cobo, S. Paliwal, and members of the Ferrer laboratory for valuable discussions and Sonia Corral Leal for drawing and advising the design of the video synopsis. We thank the Parc de Recerca Biomedica de Barcelona and University of Barcelona School of Medicine animal facilities, Center of Genomic Regulation and Imperial College London Genomics Units, and the Imperial College High Performance Computing Service. This research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. Work was funded by grants from the Wellcome Trust (WT101033 to J.F.), Medical Research Council (MR/L02036X/1 to J.F.), European Research Council Advanced Grant (789055 to J.F.), Ministerio de Ciencia e Innovacion (BFU2014-54284-R, RTI2018-095666-B-I00 to J.F., SAF2011-29530 and SAF2015-70553-R to F.X.R.) and RTICC from Instituto de Salud Carlos III (RD12/0036/0034, RD12/0036/0050) to F.X.R. M.K. was supported by a Juvenile Diabetes Research Foundation postdoctoral fellowship (3-PDF-2014-192-A-N). I.M. was supported by a Fellowship from Fundacio Bancaria La Caixa (ID 100010434) (grant number LCF/BQ/ES18/11670009). Work in CRG was supported by the CERCA Programme, Generalitat de Catalunya, and support from Ministerio de Ciencia e Innovacion to the EMBL partnership. Work at CRG and CNIO was supported by Centro de Excelencia Severo Ochoa grants SEV-2012-0208, SEV-2016-0510.