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Reprogramming pancreatic stellate cells via p53 activation: A putative target for pancreatic cancer therapy.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely dense fibrotic stroma, which contributes to tumor growth, metastasis, and drug resistance. During tumorigenesis, quiescent pancreatic stellate cells (PSCs) are activated and become major contributors to fibrosis, by increasing growth factor signaling and extracellular matrix deposition. The p53 tumor suppressor is known to restrict tumor initiation and progression through cell autonomous mechanisms including apoptosis, cell cycle arrest, and senescence. There is growing evidence that stromal p53 also exerts anti-tumor activity by paracrine mechanisms, though a role for stromal p53 in PDAC has not yet been described. Here, we demonstrate that activation of stromal p53 exerts anti-tumor effects in PDAC. We show that primary cancer-associated PSCs (caPSCs) isolated from human PDAC express wild-type p53, which can be activated by the Mdm2 antagonist Nutlin-3a. Our work reveals that p53 acts as a major regulator of PSC activation and as a modulator of PDAC fibrosis. In vitro, p53 activation by Nutlin-3a induces profound transcriptional changes, which reprogram activated PSCs to quiescence. Using immunofluorescence and lipidomics, we have also found that p53 activation induces lipid droplet accumulation in both normal and tumor-associated fibroblasts, revealing a previously undescribed role for p53 in lipid storage. In vivo, treatment of tumor-bearing mice with the clinical form of Nutlin-3a induces stromal p53 activation, reverses caPSCs activation, and decreases fibrosis. All together our work uncovers new functions for stromal p53 in PDAC.

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  • Authors+Show Affiliations

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    Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America.

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    Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America.

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    Clayton Foundation Peptide Biology Lab, Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, La Jolla, California, United States of America.

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    Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America.

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    Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, California, United States of America.

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    Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, California, United States of America.

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    Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America.

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    Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, California, United States of America.

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    Huntsman Cancer Institute, Department of Oncologic Sciences, University of Utah, Salt Lake City Utah, United States of America.

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    Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, California, United States of America.

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    Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia.

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    Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America.

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    Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America.

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    Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America.

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    Clayton Foundation Peptide Biology Lab, Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, La Jolla, California, United States of America.

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    Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, California, United States of America.

    Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America.

    Source

    PloS one 12:12 2017 pg e0189051

    MeSH

    Animals
    Carcinoma, Pancreatic Ductal
    Cellular Reprogramming
    Cholesterol Esters
    Genes, p53
    Humans
    Male
    Mice
    Mice, Inbred C57BL
    Mice, Knockout
    Pancreatic Neoplasms
    Pancreatic Stellate Cells
    Transcription, Genetic
    Triglycerides
    Tumor Cells, Cultured

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    29211796