A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer

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• dc.contributor.author Kloesch, Bernhard
• dc.contributor.author Ionasz, Vivien
• dc.contributor.author Paliwal, Sumit
• dc.contributor.author Hruschka, Natascha
• dc.contributor.author Martínez de Villarreal, Jaime
• dc.contributor.author Öllinger, Robert
• dc.contributor.author Mueller, Sebastian
• dc.contributor.author Dienes, Hans Peter
• dc.contributor.author Schindl, Martin
• dc.contributor.author Gruber, Elisabeth S.
• dc.contributor.author Stift, Judith
• dc.contributor.author Herndler-Brandstetter, Dietmar
• dc.contributor.author Lomberk, Gwen A.
• dc.contributor.author Seidler, Barbara
• dc.contributor.author Saur, Dieter
• dc.contributor.author Rad, Roland
• dc.contributor.author Urrutia, Raul A.
• dc.contributor.author Real, Francisco X.
• dc.contributor.author Martinelli, Paola
• dc.date.accessioned 2021-05-07T07:06:13Z
• dc.date.available 2021-05-07T07:06:13Z
• dc.date.issued 2022
• dc.description.abstract Objective: Molecular taxonomy of tumours is the foundation of personalised medicine and is becoming of paramount importance for therapeutic purposes. Four transcriptomics-based classification systems of pancreatic ductal adenocarcinoma (PDAC) exist, which consistently identified a subtype of highly aggressive PDACs with basal-like features, including ΔNp63 expression and loss of the epithelial master regulator GATA6. We investigated the precise molecular events driving PDAC progression and the emergence of the basal programme. Design: We combined the analysis of patient-derived transcriptomics datasets and tissue samples with mechanistic experiments using a novel dual-recombinase mouse model for Gata6 deletion at late stages of KRasG12D-driven pancreatic tumorigenesis (Gata6LateKO). Results: This comprehensive human-to-mouse approach showed that GATA6 loss is necessary, but not sufficient, for the expression of ΔNp63 and the basal programme in patients and in mice. The concomitant loss of HNF1A and HNF4A, likely through epigenetic silencing, is required for the full phenotype switch. Moreover, Gata6 deletion in mice dramatically increased the metastatic rate, with a propensity for lung metastases. Through RNA-Seq analysis of primary cells isolated from mouse tumours, we show that Gata6 inhibits tumour cell plasticity and immune evasion, consistent with patient-derived data, suggesting that GATA6 works as a barrier for acquiring the fully developed basal and metastatic phenotype. Conclusions: Our work provides both a mechanistic molecular link between the basal phenotype and metastasis and a valuable preclinical tool to investigate the most aggressive subtype of PDAC. These data, therefore, are important for understanding the pathobiological features underlying the heterogeneity of pancreatic cancer in both mice and human.
• dc.description.sponsorship Work in the lab of PM was supported by the grant P27361-B23 from the Austrian Science Grant (FWF) and by contributions from the Fellinger Krebsforschung foundation and the Ingrid Shaker-Nessmann Krebsforschungsvereinigung foundation. Patients were not involved in the design of this study. RAU and GAL were supported by The Linda T. and John A. Mellowes Endowed Innovation and Discovery Fund, the Theodore W. Batterman Family Foundation, Inc and NIH Grants: R01 DK52913 and R01 CA178627. Work in the lab of FXR was supported, in part, by grant RTI2018-101071-B-I00 (Ministerio de Ciencia, Innovación y Universidades, Madrid, Spain). CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510.
• dc.format.mimetype application/pdf
• dc.identifier.citation Kloesch B, Ionasz V, Paliwal S, Hruschka N, Martinez de Villarreal J, Öllinger R, Mueller S, Dienes HP, Schindl M, Gruber ES, Stift J, Herndler-Brandstetter D, Lomberk GA, Seidler B, Saur D, Rad R, Urrutia RA, Real FX, Martinelli P. A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer. Gut. 2022;71(4):766-77. DOI: 10.1136/gutjnl-2020-321397
• dc.identifier.doi http://dx.doi.org/10.1136/gutjnl-2020-321397
• dc.identifier.issn 0017-5749
• dc.identifier.uri http://hdl.handle.net/10230/47346
• dc.language.iso eng
• dc.publisher BMJ Publishing Group
• dc.relation.ispartof Front Psychiatry. 2022;71(4):766-77
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-101071-B-I00
• dc.rights © Author(s) (or their employer(s)) 2021. 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 Epithelial differentiation
• dc.subject.keyword Molecular mechanisms
• dc.subject.keyword Pancreatic cancer
• dc.title A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion