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Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment

Authors

  • Vanessa Rausch,

    1. Molecular OncoSurgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
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    • These authors contributed equally to this study.

  • Li Liu,

    1. Molecular OncoSurgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
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    • These authors contributed equally to this study.

  • Anja Apel,

    1. Molecular OncoSurgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
    Current affiliation:
    1. Naturwissenschaftliches und Medizinisches Institut, Universität Tübingen, Reutlingen, Germany.
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    • These authors contributed equally to this study.

  • Theresa Rettig,

    1. Molecular OncoSurgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
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  • Jury Gladkich,

    1. Molecular OncoSurgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
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  • Sabrina Labsch,

    1. Molecular OncoSurgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
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  • Georgios Kallifatidis,

    1. Molecular OncoSurgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
    Current affiliation:
    1. Marine Biomedical and Biotechnology Research, Harbor Branch Oceanographic Institute at Florida Atlantic University, Miami, USA.
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  • Adam Kaczorowski,

    1. Molecular OncoSurgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
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  • Ariane Groth,

    1. Molecular OncoSurgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
    Current affiliation:
    1. University of Frankfurt, Institute of Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany.
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  • Wolfgang Gross,

    1. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Experimental Surgery, University of Heidelberg and German Cancer Research Centre, Germany
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  • Martha M Gebhard,

    1. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Experimental Surgery, University of Heidelberg and German Cancer Research Centre, Germany
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  • Peter Schemmer,

    1. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
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  • Jens Werner,

    1. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
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  • Alexei V Salnikov,

    1. Molecular OncoSurgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Translational Immunology Unit, German Cancer Research Centre, Heidelberg, Germany
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  • Hanswalter Zentgraf,

    1. Electron Microscopy, German Cancer Research Centre, Heidelberg, Germany
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  • Markus W Büchler,

    1. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
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  • Ingrid Herr

    Corresponding author
    1. Molecular OncoSurgery, University of Heidelberg and German Cancer Research Centre, Germany
    2. Department of General Surgery, University of Heidelberg and German Cancer Research Centre, Germany
    • Experimental Surgery, Department of General Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 365, 69120 Heidelberg, Germany.
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  • No conflicts of interest were declared.

Abstract

Involvement of dysregulated autophagy in cancer growth and progression has been shown in different tumour entities, including pancreatic ductal adenocarcinoma (PDA). PDA is an extremely aggressive tumour characterized by a small population of highly therapy-resistant cancer stem cells (CSCs) capable of self-renewal and migration. We examined whether autophagy might be involved in the survival of CSCs despite nutrition and oxygen deprivation typical for the hypoxic tumour microenvironment of PDA. Immunohistochemistry revealed that markers for hypoxia, CSCs and autophagy are co-expressed in patient-derived tissue of PDA. Hypoxia starvation (H/S) enhanced clonogenic survival and migration of established pancreatic cancer cells with stem-like properties (CSCequation image, while pancreatic tumour cells with fewer stem cell markers (CSCequation image did not survive these conditions. Electron microscopy revealed more advanced autophagic vesicles in CSCequation image cells, which exhibited higher expression of autophagy-related genes under normoxic conditions and relative to CSCequation image cells, as found by RT-PCR and western blot analysis. LC3 was already fully converted to the active LC3-II form in both cell lines, as evaluated by western blot and detection of accumulated GFP-LC3 protein by fluorescence microscopy. H/S increased formation of autophagic and acid vesicles, as well as expression of autophagy-related genes, to a higher extent in CSCequation image cells. Modulation of autophagy by inhibitors and activators resensitized CSCequation image to apoptosis and diminished clonogenicity, spheroid formation, expression of CSC-related genes, migratory activity and tumourigenicity in mice. Our data suggest that enhanced autophagy levels may enable survival of CSCequation image cells under H/S. Interference with autophagy-activating or -inhibiting drugs disturbs the fine-tuned physiological balance of enhanced autophagy in CSC and switches survival signalling to suicide. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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