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Pancreas
Original research
Discovery and 3D imaging of a novel ΔNp63-expressing basal cell type in human pancreatic ducts with implications in disease
  1. Sandrina Martens1,
  2. Katarina Coolens1,
  3. Mathias Van Bulck1,
  4. Tatjana Arsenijevic2,3,
  5. Joan Casamitjana4,5,
  6. Angel Fernandez Ruiz4,5,
  7. Abdessamad El Kaoutari6,7,
  8. Jaime Martinez de Villareal8,
  9. Hediel Madhloum1,
  10. Farzad Esni9,
  11. Yves Heremans10,
  12. Gunter Leuckx10,
  13. Harry Heimberg10,
  14. Luc Bouwens11,
  15. Patrick Jacquemin12,
  16. Diedert Luc De Paep13,
  17. Peter in't Veld13,
  18. Nicky D'Haene14,
  19. Christelle Bouchart15,
  20. Nelson Dusetti6,
  21. Jean-Luc Van Laethem2,3,
  22. Wim Waelput16,17,
  23. Pierre Lefesvre16,17,
  24. Francisco X Real8,
  25. Meritxell Rovira4,5,
  26. Ilse Rooman1
  1. 1Laboratory of Medical and Molecular Oncology, Vrije Universiteit Brussel, Brussel, Belgium
  2. 2Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Bruxelles, Belgium
  3. 3Hopital Erasme Service de Gastroenterologie d'Hepato-Pancreatologie et d'Oncologie Digestive, Bruxelles, Belgium
  4. 4Department of Physiological Science, School of Medicine, University of Barcelona (UB), L’Hospitalet de Llobregat, Spain
  5. 5Pancreas Regeneration: Pancreatic Progenitors and Their Niche Group, Regenerative Medicine Program, P-CMR[C], Institut d’Investigació Biomèdica de Bellvitge ‐ IDIBELL, L’Hospitalet de Llobregat, Spain
  6. 6Centre de Recherche en Cancérologie de Marseille - CRCM, INSERM UMR1068, CRCM, Marseille, France
  7. 7COMPO Unit, Centre de Recherche en Cancérologie de Marseille, Marseille, France
  8. 8Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre, Madrid, Spain
  9. 9Division of Pediatric General and Thoracic Surgery, University of Pittsburgh Department of Surgery, Pittsburgh, Pennsylvania, USA
  10. 10Laboratory of Beta Cell Neogenesis, Vrije Universiteit Brussel, Brussel, Belgium
  11. 11Cell Differentiation Laboratory, Vrije Universiteit Brussel, Brussel, Belgium
  12. 12Institut de Duve, Université catholique de Louvain, Louvain-la-Neuve, Belgium
  13. 13Diabetes Research Center, Vrije Universiteit Brussel, Brussel, Belgium
  14. 14Department of Pathology, Hopital Erasme, Bruxelles, Belgium
  15. 15Department of Radiation-Oncology, Jules Bordet Institute, Bruxelles, Belgium
  16. 16Department of Pathology, UZ Brussel, Brussel, Belgium
  17. 17Department of Pathology, Vrije Universiteit Brussel, Brussel, Belgium
  1. Correspondence to Dr Ilse Rooman, Laboratory of Medical and Molecular Oncology, Vrije Universiteit Brussel, Brussel, Belgium; irooman{at}vub.be

Abstract

Objective The aggressive basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) harbours a ΔNp63 (p40) gene expression signature reminiscent of a basal cell type. Distinct from other epithelia with basal tumours, ΔNp63+ basal cells reportedly do not exist in the normal pancreas.

Design We evaluated ΔNp63 expression in human pancreas, chronic pancreatitis (CP) and PDAC. We further studied in depth the non-cancerous tissue and developed a three-dimensional (3D) imaging protocol (FLIP-IT, Fluorescence Light sheet microscopic Imaging of Paraffin-embedded or Intact Tissue) to study formalin-fixed paraffin-embedded samples at single cell resolution. Pertinent mouse models and HPDE cells were analysed.

Results In normal human pancreas, rare ΔNp63+ cells exist in ducts while their prevalence increases in CP and in a subset of PDAC. In non-cancer tissue, ΔNp63+ cells are atypical KRT19+ duct cells that overall lack SOX9 expression while they do express canonical basal markers and pertain to a niche of cells expressing gastrointestinal stem cell markers. 3D views show that the basal cells anchor on the basal membrane of normal medium to large ducts while in CP they exist in multilayer dome-like structures. In mice, ΔNp63 is not found in adult pancreas nor in selected models of CP or PDAC, but it is induced in organoids from larger Sox9low ducts. In HPDE, ΔNp63 supports a basal cell phenotype at the expense of a classical duct cell differentiation programme.

Conclusion In larger human pancreatic ducts, basal cells exist. ΔNp63 suppresses duct cell identity. These cells may play an important role in pancreatic disease, including PDAC ontogeny, but are not present in mouse models.

  • pancreas
  • stem cells
  • cancer
  • development genes
  • imaging

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All relevant data can be requested by contacting the corresponding author.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2020-322874

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    Data availability statement

    Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All relevant data can be requested by contacting the corresponding author.

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    Footnotes

    • SM, KC and MVB are joint first authors.

    • Twitter @SamadELKA, @TxellRovira

    • SM, KC and MVB contributed equally.

    • JC and AFR contributed equally.

    • Contributors This study was conceptualised and designed by SM, KC, MVB, MR and IR. SM, KC, MVB, TA, AFR, JC, AEK, HM, YH, GL, DLDP, ND'H, CB and MR performed experiments, data collection and interpretation. FE, HH, LB, PJ, PiV, ND, J-LVL, WW, PL, FXR and MR provided intellectual input and important samples. SM, KC and IR wrote the manuscript, and all authors edited the manuscript. KC, SM and MVB contributed equally to this paper. JC and AFR contributed equally to this paper as well.

    • Funding Work in the LMMO laboratory was supported by Stichting tegen Kanker Translational & Clinical Research Grants 2018 #2092. IR is a recipient of an Odysseus I fellowship of the Research Foundation-Flanders (FWO). MVB was financially supported by the Award Cancer Research-Oncology Center Vrije Universiteit Brussel, funded by the bequests of late Ms Esther Desmedt and late Ms Irma Noëand and Wetenschappelijk Fonds Willy Gepts of the UZ Brussel. KC is a recipient of a PhD Fellowship of the FWO (Grant ID 1157221N). Work in the laboratory of FXR is supported, in part, by grant RTI2018-101071-B-I00 from Ministerio de Ciencia e Innovación (Madrid, Spain) (co-funded by the ERDF-EU). CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510. M.R, A.F and J.C reserach was supported by RYC-2017-21950 (AEI/EFS,UE) and SAF2015-73226-JIN (AEI/FEDER, UE). We thank CIBER-BBN and CERCA Programme / Generalitat de Catalunya for IDIBELL institutional support.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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