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      Homotypic cell cannibalism, a cell-death process regulated by the nuclear protein 1, opposes to metastasis in pancreatic cancer

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          Abstract

          Pancreatic adenocarcinoma (PDAC) is an extremely deadly disease for which all treatments available have failed to improve life expectancy significantly. This may be explained by the high metastatic potential of PDAC cells, which results from their dedifferentiation towards a mesenchymal phenotype. Some PDAC present cell-in-cell structures whose origin and significance are currently unknown. We show here that cell-in-cells form after homotypic cell cannibalism (HoCC). We found PDAC patients whose tumours display HoCC develop less metastasis than those without. In vitro, HoCC was promoted by inactivation of the nuclear protein 1 (Nupr1), and was enhanced by treatment with transforming growth factor β. HoCC ends with death of PDAC cells, consistent with a metastasis suppressor role for this phenomenon. Hence, our data indicates a protective role for HoCC in PDAC and identifies Nupr1 as a molecular regulator of this process.

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          Epithelial-mesenchymal transitions in development and disease.

          Jean Paul Thiery, Hervé Acloque, Ruby Y J Huang … (2009)
          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma.

            Andrew Aguirre, Nabeel Bardeesy, Manisha Sinha … (2003)
            Pancreatic ductal adenocarcinoma ranks among the most lethal of human malignancies. Here, we assess the cooperative interactions of two signature mutations in mice engineered to sustain pancreas-specific Cre-mediated activation of a mutant Kras allele (KrasG12D) and deletion of a conditional Ink4a/Arf tumor suppressor allele. The phenotypic impact of KrasG12D alone was limited primarily to the development of focal premalignant ductal lesions, termed pancreatic intraepithelial neoplasias (PanINs), whereas the sole inactivation of Ink4a/Arf failed to produce any neoplastic lesions in the pancreas. In combination, KrasG12D expression and Ink4a/Arf deficiency resulted in an earlier appearance of PanIN lesions and these neoplasms progressed rapidly to highly invasive and metastatic cancers, resulting in death in all cases by 11 weeks. The evolution of these tumors bears striking resemblance to the human disease, possessing a proliferative stromal component and ductal lesions with a propensity to advance to a poorly differentiated state. These findings in the mouse provide experimental support for the widely accepted model of human pancreatic adenocarcinoma in which activated KRAS serves to initiate PanIN lesions, and the INK4A/ARF tumor suppressors function to constrain the malignant conversion of these PanIN lesions into lethal ductal adenocarcinoma. This faithful mouse model may permit the systematic analysis of genetic lesions implicated in the human disease and serve as a platform for the identification of early disease markers and for the efficient testing of novel therapies.
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              Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse.

              Lynda Chin, Nabeel Bardeesy, M Redston … (2006)
              Activating KRAS mutations and p16(Ink4a) inactivation are near universal events in human pancreatic ductal adenocarcinoma (PDAC). In mouse models, Kras(G12D) initiates formation of premalignant pancreatic ductal lesions, and loss of either Ink4a/Arf (p16(Ink4a)/p19(Arf)) or p53 enables their malignant progression. As recent mouse modeling studies have suggested a less prominent role for p16(Ink4a) in constraining malignant progression, we sought to assess the pathological and genomic impact of inactivation of p16(Ink4a), p19(Arf), and/or p53 in the Kras(G12D) model. Rapidly progressive PDAC was observed in the setting of homozygous deletion of either p53 or p16(Ink4a), the latter with intact germ-line p53 and p19(Arf) sequences. Additionally, Kras(G12D) in the context of heterozygosity either for p53 plus p16(Ink4a) or for p16(Ink4a)/p19(Arf) produced PDAC with longer latency and greater propensity for distant metastases relative to mice with homozygous deletion of p53 or p16(Ink4a)/p19(Arf). Tumors from the double-heterozygous cohorts showed frequent p16(Ink4a) inactivation and loss of either p53 or p19(Arf). Different genotypes were associated with specific histopathologic characteristics, most notably a trend toward less differentiated features in the homozygous p16(Ink4a)/p19(Arf) mutant model. High-resolution genomic analysis revealed that the tumor suppressor genotype influenced the specific genomic patterns of these tumors and showed overlap in regional chromosomal alterations between murine and human PDAC. Collectively, our results establish that disruptions of p16(Ink4a) and the p19(ARF)-p53 circuit play critical and cooperative roles in PDAC progression, with specific tumor suppressor genotypes provocatively influencing the tumor biological phenotypes and genomic profiles of the resultant tumors.
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                Author and article information

                Journal
                Journal ID (nlm-ta): EMBO Mol Med
                Journal ID (iso-abbrev): EMBO Mol Med
                Journal ID (publisher-id): emmm
                Title: EMBO Molecular Medicine
                Publisher: WILEY-VCH Verlag (Weinheim )
                ISSN (Print): 1757-4676
                ISSN (Electronic): 1757-4684
                Publication date (Print): September 2012
                Publication date (Electronic): 23 July 2012
                Volume: 4
                Issue: 9
                Pages: 964-979
                Affiliations
                [1 ]INSERM U1068, CRCM, Cell Stress Marseille, France
                [2 ]Institut Paoli-Calmettes Marseille, France
                [3 ]Aix-Marseille University Marseille, France
                [4 ]CNRS, UMR7258, CRCM Marseille, France
                [5 ]Molecular Endocrinology and Oncology Research Center, CHUL Research Center Quebec, Canada
                [6 ]INSERM U1052 Lyon, France
                [7 ]CNRS UMR 5286 Lyon, France
                [8 ]Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard Lyon, France
                [9 ]University of Lyon Lyon, France
                [10 ]Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic Rochester, USA
                [11 ]INSERM, U848 Villejuif, France
                [12 ]Metabolomics Platform, Institut Gustave Roussy Villejuif, France
                [13 ]Centre de Recherche des Cordeliers Paris, France
                [14 ]Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP Paris, France
                [15 ]Université Paris Descartes Paris 5, Paris, France
                Author notes
                * Corresponding author: Tel : +33 491 828803; Fax: +33 491 82886083; E-mail: juan.iovanna@ 123456inserm.fr
                Article
                DOI: 10.1002/emmm.201201255
                PMC ID: 3491828
                PubMed ID: 22821859
                SO-VID: 2cac86d9-86c2-4c05-8b43-78ade625b211
                Copyright © Copyright © 2012 EMBO Molecular Medicine
                License:

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                Date received : 03 February 2012
                Date revision received : 15 June 2012
                Date accepted : 20 June 2012
                Categories
                Subject: Research Articles

                ScienceOpen disciplines: Molecular medicine
                Keywords: nupr1,cell cannibalism,metastasis,tgfβ,pancreatic cancer
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: nupr1, cell cannibalism, metastasis, tgfβ, pancreatic cancer

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