{
  "abstract": "Background The efficacy of pharmacological glycogen synthase kinase-3β (GSK3β) inhibition is currently being investigated in unselected cohorts of metastatic pancreatic ductal adenocarcinoma (PDAC). Here, we sought to determine the clinical significance of nuclear GSK3β accumulation in patients with resectable PDAC.Objective This study aimed to explore the therapeutic potential and underlying mechanisms of GSK3β pathway disruption in PDAC with enriched nuclear GSK3β levels.Design We investigated the activation and function of GSK3β and its downstream transcription factor NFATc1 in tumour recurrence, growth and resistance using human PDAC tissues, patient-derived organoids and tumour cells, PDAC explants, cell lines and murine models. GSK3β signalling was disrupted using genetic and pharmacological approaches. Live-cell imaging, proliferation, homologous recombination (HR) repair and comet assays, messenger RNA sequencing and chromatin immunoprecipitation were used to explore GSK3β-NFATc1 signalling-mediated target gene regulation in DNA repair, growth and resistance.Results Nuclear GSK3β accumulates in a subset of resected PDAC and promotes proliferation and DNA repair through NFATc1. The GSK3β high/NFATc1high subtype accounts for 14% of resected PDAC and is associated with rapid tumour recurrence and poor survival. The GSK3β-NFATc1 signalling pathway contributes to cisplatin resistance by inducing BRCA genes transcription, which facilitates HR-mediated DNA double-strand breaks (DSBs) repair. Disruption of the GSK3β-NFATc1 axis impairs HR-driven DSB repair, increasing cisplatin sensitivity in vitro and in preclinical PDAC models.Conclusion We have identified a highly aggressive GSK3β high/NFATc1high subtype that predicts early recurrence, poor survival and cisplatin resistance in PDAC. This subtype reveals new treatment vulnerabilities suggesting that patients with PDAC may benefit from stratification-based tailored treatment strategies.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Muhammad Umair Latif"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Xueang Liu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany",
        "Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Aiko Bockelmann"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Laura Huhnold"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Geske Elisabeth Schmidt"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Lukas Klein"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Xueyuan Zhao"
    },
    {
      "affiliations": [
        "General and Visceral Surgery, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Lena-Christin Conradi"
    },
    {
      "affiliations": [
        "Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany",
        "Department of Medical Bioinformatics, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Karly Conrads"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Anna Lena Weber"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Sercan Mercan"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Kristina Reutlinger"
    },
    {
      "affiliations": [
        "Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany",
        "Department for Molecular Oncology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Atmika Paul"
    },
    {
      "affiliations": [
        "Robert Bosch Centre for Tumour Diseases, Stuttgart, BW, Germany"
      ],
      "name": "Zeynab Najafova"
    },
    {
      "affiliations": [
        "Robert Bosch Centre for Tumour Diseases, Stuttgart, BW, Germany"
      ],
      "name": "Steven A Johnsen"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Zuriñe Bonilla Del Rio"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Frederike Penz"
    },
    {
      "affiliations": [
        "Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany",
        "Institute of Pathology, University Medical Center Göttingen, Göttingen, NDS, Germany"
      ],
      "name": "Jovan Todorovic"
    },
    {
      "affiliations": [
        "Department for Molecular Oncology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Holger Bastians"
    },
    {
      "affiliations": [
        "Department of Medical Bioinformatics, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Tim Beissbarth"
    },
    {
      "affiliations": [
        "Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany",
        "Department of Medical Informatics, University Medical Center Göttingen, Göttingen, NDS, Germany"
      ],
      "name": "Ulrich Sax"
    },
    {
      "affiliations": [
        "Institute of Toxicology, University Medical Center Mainz, Mainz, Germany",
        "Department of Oral Pathology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt, Al-Mansura, Egypt"
      ],
      "name": "Ramy Ashry"
    },
    {
      "affiliations": [
        "Institute of Toxicology, University Medical Center Mainz, Mainz, Germany"
      ],
      "name": "Oliver H Krämer"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany",
        "Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Elisabeth Hessmann"
    },
    {
      "affiliations": [
        "Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany",
        "Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Günter Schneider"
    },
    {
      "affiliations": [
        "Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany",
        "Institute of Pathology, University Medical Center Göttingen, Göttingen, NDS, Germany"
      ],
      "name": "Philipp Stroebel"
    },
    {
      "affiliations": [
        "Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"
      ],
      "name": "Ivan Bogeski"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany",
        "Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Shiv K Singh"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany",
        "Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Lower Saxony, Germany"
      ],
      "name": "Volker Ellenrieder"
    }
  ],
  "title": "GSK3βhigh/NFATc1high subtype targeting overcomes therapy resistance in pancreatic cancer through transcriptional induction of homologous recombination repair",
  "uid": "3b2e8ec7-5a89-5e3a-930d-42cd9baa27be"
}