Discovery and 3D imaging of a novel ΔNp63-expressing basal cell type in human pancreatic ducts with implications in disease

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• dc.contributor.author Martens, Sandrina
• dc.contributor.author Real, Francisco X.
• dc.contributor.author Rooman, Ilse
• dc.date.accessioned 2021-10-14T06:21:24Z
• dc.date.available 2021-10-14T06:21:24Z
• dc.date.issued 2022
• dc.description.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.
• dc.description.sponsorship 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Martens S, Coolens K, Van Bulck M, Arsenijevic T, Casamitjana J, Fernandez Ruiz A et al. Discovery and 3D imaging of a novel ΔNp63-expressing basal cell type in human pancreatic ducts with implications in disease. Gut. 2022;71(10):2030-42. DOI: 10.1136/gutjnl-2020-322874
• dc.identifier.doi http://dx.doi.org/10.1136/gutjnl-2020-322874
• dc.identifier.issn 0017-5749
• dc.identifier.uri http://hdl.handle.net/10230/48644
• dc.language.iso eng
• dc.publisher BMJ Publishing Group
• dc.relation.ispartof Gut. 2022;71(10):2030-42
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-101071-B-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-73226-JIN
• dc.rights © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 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/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword Cancer
• dc.subject.keyword Development genes
• dc.subject.keyword Imaging
• dc.subject.keyword Pancreas
• dc.subject.keyword Stem cells
• dc.title Discovery and 3D imaging of a novel ΔNp63-expressing basal cell type in human pancreatic ducts with implications in disease
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion