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Simple Summary: Only a limited number of murine mesothelioma cell lines have been developed to date. We sought to expand this number and to characterize the models in detail to enable studying mesothelioma biology in vivo. Two cell lines were identified as showing well-defined mesothelioma biomarkers and being suitable for preclinical use. In the course of our studies, we observed a mixed phenotype of chromosomal instability and microsatellite instability not previously reported in mouse models. Moreover, microsatellite markers were detectable in the plasma of tumor-bearing animals, which potentially can be used as non-invasive biomarkers for early cancer detection and monitoring the effects of interventions. Malignant mesothelioma (MMe) is a rare malignancy originating from the linings of the pleural, peritoneal and pericardial cavities. The best-defined risk factor is exposure to carcinogenic mineral fibers (e.g., asbestos). Genomic studies have revealed that the most frequent genetic lesions in human MMe are mutations in tumor suppressor genes. Several genetically engineered mouse models have been generated by introducing the same genetic lesions found in human MMe. However, most of these models require specialized breeding facilities and long-term exposure of mice to asbestos for MMe development. Thus, an alternative model with high tumor penetrance without asbestos is urgently needed. We characterized an orthotopic model using MMe cells derived from Cdkn2a+/−;Nf2+/− mice chronically injected with asbestos. These MMe cells were tumorigenic upon intraperitoneal injection. Moreover, MMe cells showed mixed chromosome and microsatellite instability, supporting the notion that genomic instability is relevant in MMe pathogenesis. In addition, microsatellite markers were detectable in the plasma of tumor-bearing mice, indicating a potential use for early cancer detection and monitoring the effects of interventions. This orthotopic model with rapid development of MMe without asbestos exposure represents genomic instability and specific molecular targets for therapeutic or preventive interventions to enable preclinical proof of concept for the intervention in an immunocompetent setting. [ABSTRACT FROM AUTHOR]