{
  "abstract": "Background Chronic pancreatitis (CP) is a risk factor for pancreatic cancer, with inherited cases conferring a markedly increased risk. The underlying mechanisms driving malignant transformation by CP remain poorly understood.Objective Combining a recently developed mouse model of CP carrying the human carboxypeptidase A1 ( CPA1) p.N256K mutation with the established KrasG12D pancreatic cancer model, we characterised mechanisms linking chronic inflammation to early pancreatic carcinogenesis.Design We crossed Cpa1 N256K mice (Cpa1) with Ptf1aCre;KrasLSL-G12D (KC). In Cre, Cpa1, KC and KC-Cpa1 mice, we performed phenotypical characterisation at five early time points and in an ageing cohort. Assessment of histology combined with both RNA-sequencing and single-cell RNA-sequencing was performed to analyse metaplasia, preneoplastic lesions and cellular heterogeneity.Results KC-Cpa1 pancreata displayed a stark increase in remodelling, fibrosis and formation of metaplastic lesions as compared with KC. Cpa1 N256K induced extensive plasticity in both the acinar and ductal compartment, including an early acinar-to-ductal metaplasia state in acinar cells characterised by an upregulation of endoplasmic reticulum stress markers and an inflammatory ductal phenotype (iDucts). We characterised the complex cell-cell communication networks underlying both pancreatic inflammation and early carcinogenesis, revealing disease-specific signalling between ductal cells, granulocytes and fibroblasts.Conclusions The humanised KC-Cpa1 mouse model reveals the interplay of inflammation in hereditary CP and carcinogenesis. Cpa1 N256K -induced plasticity in acinar and ductal cells, inflammation and cell-cell interaction networks cooperate with KrasG12D in early pancreatic carcinogenesis.",
  "authors": [
    {
      "affiliations": [
        "Department of Internal Medicine I, University Medicine Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Tanvi Vikrant Inamdar"
    },
    {
      "affiliations": [
        "Department of Internal Medicine I, University Medicine Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Ferdinand Krannich"
    },
    {
      "affiliations": [
        "Department of Internal Medicine I, University Medicine Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Nico Hesselbarth"
    },
    {
      "affiliations": [
        "Department of Internal Medicine I, University Medicine Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Atul Verma"
    },
    {
      "affiliations": [
        "Department of Internal Medicine I, University Medicine Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Teresa Vauti"
    },
    {
      "affiliations": [
        "Department of Internal Medicine I, University Medicine Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Mariami Helena Jasaszwili"
    },
    {
      "affiliations": [
        "Institute of Molecular Medicine, Section for Molecular Medicine of Signal Transduction, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Ghanem El Kassem"
    },
    {
      "affiliations": [
        "Institute of Molecular Medicine, Section for Molecular Medicine of Signal Transduction, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Jasmine Hillmer"
    },
    {
      "affiliations": [
        "Department of Internal Medicine I, University Medicine Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Tom Kaune"
    },
    {
      "affiliations": [
        "Institute of Molecular Medicine, Section for Molecular Medicine of Signal Transduction, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Michael Boettcher"
    },
    {
      "affiliations": [
        "Department of Medicine II, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany",
        "Institute for Tumor Immunology, University Medicine Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Ivonne Regel"
    },
    {
      "affiliations": [
        "Department of Internal Medicine I, University Medicine Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Heidi Griesmann"
    },
    {
      "affiliations": [
        "Institute of Pathology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany"
      ],
      "name": "Irene Esposito"
    },
    {
      "affiliations": [
        "Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Markus Glaß"
    },
    {
      "affiliations": [
        "Institute of Pathology, Martin Luther University Halle-Wittenberg, University Medical Center, Halle (Saale), Germany"
      ],
      "name": "Monika Hämmerle"
    },
    {
      "affiliations": [
        "Dept. of Internal Medicine IV, Heidelberg University Hospital, Heidelberg, Germany"
      ],
      "name": "Patrick Michl"
    },
    {
      "affiliations": [
        "Department of Internal Medicine I, University Medicine Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Helmut Laumen"
    },
    {
      "affiliations": [
        "Department of Internal Medicine I, University Medicine Halle, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Jonas Rosendahl"
    }
  ],
  "title": "Hereditary chronic pancreatitis induced plasticity cooperates with mutant Kras in early pancreatic carcinogenesis",
  "uid": "f8460163-2120-5aac-999f-7a1a1b39fae6"
}