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Daniel J. Murphy



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    MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA23.06 - Development of a Novel Genetically Engineered Mouse Model of Malignant Pleural Mesothelioma (Now Available) (ID 2506)

      14:30 - 16:00  |  Author(s): Daniel J. Murphy

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive neoplasm strongly associated with inhalation of asbestos. MPM is difficult to diagnose and typically occurs after long latency period. Most of the studies are restricted to the end-stage disease and little is known about pre-malignant disease. Efforts to develop targeted therapeutic strategies based on cell culture have largely failed. Our aim was to develop a novel genetically engineered mouse model that combines deletion of the major tumour suppressors lost in human MPM with intra-pleural injection of asbestos. This model will allow us to investigate how mutagenesis combines with fibre-induced inflammation to drive disease evolution.

      Method

      We used genetic engineering to develop an accelerated mesothelioma mouse model combining pleural-restricted, CRE-mediated deletion of NF2, Tp53 (Tp53 is lost in c.10% of human MPM) and full-body knock-out of Cdkn2a with intra-pleural injection of asbestos recapitulating the disease-relevant inflammatory microenvironment. We used immunohistochemistry to analyse the tissue and the lesions.

      Result

      Intra-pleural injection of asbestos dramatically accelerates mesothelioma development in mice triple deleted for NF2, Cdkn2a and Tp53, with all such mice succumbing to malignant disease within 3-4 months (Figure 1). These mice develop malignant lesions in the mesothelial lining of the thoracic cavity accompanied with pleural effusion showing high similarity with human malignant mesothelioma. IHC analysis showes positive staining for mesothelioma markers, e.g. pancytokeratin, vimentin and WT-1. Positive macrophage staining (F4/80) strongly indicates involvement of inflamatory component.sc_pic.png

      Conclusion

      In our model, we combined conditional mouse genetics with dose-defined exposure to asbestos to mimic development of human MPM. Our system provides unique insights into the critical transition from pre-malignancy to MPM and will allow us to test emerging therapeutic interventions in the most physiologically relevant pre-clinical setting possible.

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