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

Autor:	Kloesch B; Institute of Cancer Research, Departmet of Medicine I, Medical University of Vienna, Wien, Austria.; Comprehensive Cancer Center, Medical University Vienna, Wien, Austria., Ionasz V; Institute of Cancer Research, Departmet of Medicine I, Medical University of Vienna, Wien, Austria.; Comprehensive Cancer Center, Medical University Vienna, Wien, Austria., Paliwal S; Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), CIBERONC, Madrid, Spain., Hruschka N; Institute of Cancer Research, Departmet of Medicine I, Medical University of Vienna, Wien, Austria.; Comprehensive Cancer Center, Medical University Vienna, Wien, Austria., Martinez de Villarreal J; Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), CIBERONC, Madrid, Spain., Öllinger R; Center for Translational Cancer Research, Technical University Munich, Munich, Germany.; Institute of Molecular Oncology and Functional Genomics, Technical University Munich, Munich, Germany., Mueller S; Center for Translational Cancer Research, Technical University Munich, Munich, Germany.; Institute of Molecular Oncology and Functional Genomics, Technical University Munich, Munich, Germany., Dienes HP; Department of Pathology, Medical University of Vienna, Vienna, Austria., Schindl M; Comprehensive Cancer Center, Medical University Vienna, Wien, Austria.; Division of General Surgery, Medical University of Vienna, Wien, Austria., Gruber ES; Comprehensive Cancer Center, Medical University Vienna, Wien, Austria.; Division of General Surgery, Medical University of Vienna, Wien, Austria., Stift J; Department of Pathology, Medical University of Vienna, Vienna, Austria., Herndler-Brandstetter D; Institute of Cancer Research, Departmet of Medicine I, Medical University of Vienna, Wien, Austria.; Comprehensive Cancer Center, Medical University Vienna, Wien, Austria., Lomberk GA; Genomics Sciences and Precision Medicine Center and Division of Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Seidler B; Center for Translational Cancer Research, Technical University Munich, Munich, Germany.; Department of Medicine II, Klinikum rechts der Isar, Technical University Munich, Munich, Gemany., Saur D; Center for Translational Cancer Research, Technical University Munich, Munich, Germany.; Department of Medicine II, Klinikum rechts der Isar, Technical University Munich, Munich, Gemany.; German Cancer Consortium (DKTK), German Cancer Research Consortium (DKFZ), Heidelberg, Germany., Rad R; Center for Translational Cancer Research, Technical University Munich, Munich, Germany.; Department of Medicine II, Klinikum rechts der Isar, Technical University Munich, Munich, Gemany.; German Cancer Consortium (DKTK), German Cancer Research Consortium (DKFZ), Heidelberg, Germany., Urrutia RA; Genomics Sciences and Precision Medicine Center and Division of Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Real FX; Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), CIBERONC, Madrid, Spain.; Departament de Ciènces Experimental i de la Salut, Pompeu Fabra University, Barcelona, Spain., Martinelli P; Institute of Cancer Research, Departmet of Medicine I, Medical University of Vienna, Wien, Austria paola.martinelli@boehringer-ingelheim.com.; Comprehensive Cancer Center, Medical University Vienna, Wien, Austria.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2022 Apr; Vol. 71 (4), pp. 766-777. Date of Electronic Publication: 2021 Apr 12.
DOI:	10.1136/gutjnl-2020-321397
Abstrakt:	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 KRas G12D -driven pancreatic tumorigenesis (Gata6 LateKO ). 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. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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