PO-223 Modelling malignant mesothelioma in mice: a critical role for BAP1 loss

Abstract

Introduction Malignant mesothelioma(MM) is a highly aggressive tumour of serosal surfaces. The vast majority of cases of mesothelioma are linked to asbestos exposure. Loss of BAP1, NF2, and CDKN2ABtumour suppressor gene function is frequently observed in malignant mesothelioma. There is limited treatment option available with cisplatin/pemetrexed as the main frontline therapy with modest survival advantage. There is an urgent need of preclinical models that are fast, reproducible and that recapitulates human disease to test new treatment modalities. Here, we describe a mouse model of MM based upon the co-deletion of Bap1, Nf2, and Cdkn2ab. Material and methods Mesotheliomas were induced by deleting Bap1, Nf2, and Cdkn2ab in the thoracic cavity of mice. The tumour and its microenvironment were characterised histologically. Furthermore, we performed gene expression, chromatin profiling and drug response in tumor-derived primary cells. In addition, we employed this autochthonous model for testing current standard of care as a proof of concept treatment. Results and discussions The combined inactivation of Bap1, Nf2, and Cdkn2ab in thoracic cavity led to a highly aggressive primarily epithelioid mesothelioma with histopathological features and gene expression profile similar to human MM. This includes the distinct inflammatory phenotype. Bap1 deletion accelerated mesothelioma dramatically when combined with Nf2, Cdkn2a, Cdkn2b and p19Arf disruption (hereafter refer as BNC loss). The accelerated tumour development is invariably connected with EZH2 mediated redistribution of H2K27me3 towards promoter sites, and activation of the PI3K, MAPK pathway. The primary cells derived from mouse mesothelioma showed drug response profile similar to those observed in human MM. Treatment of BNC tumours with cisplatin and pemetrexed, the current frontline treatment modestly prolonged survival of the mice. Conclusion We have developed a mouse model that is fast and recapitulates human mesothelioma. The mouse model is an ideal model system to study the biology and pathogenesis of mesothelioma. Furthermore, the immune-competence of this model, and the fast and synchronous tumour onset makes it very suitable to design and validate new treatment regimens for this deadly disease.