Animal models of mesothelioma: Malignant mesothelioma (MM) is a highly aggressive, treatment- unresponsive cancer usually caused by exposure to asbestos such as that found in Ambler, Pennsylvania. With estimates of >20 million individuals at risk worldwide, new approaches in disease management and prevention are badly needed. The genetic basis for MM has historically focused on somatic mutations of the tumor suppressor genes CDKN2A and NF2 as key alterations influencing initiation and progression. Very recently, the BAP1 ubiquitin carboxy-terminal hydrolase, has been strongly implicated as a major player in MM based on genetic analyses. Germline BAP1 mutations were found in families with a high incidence of MM and other cancers, and somatic BAP1 alterations occurred in MMs, consistent with biallelic inactivation of a tumor suppressor. Moreover, somatic BAP1 mutations are common in sporadic MMs, often in combination with alterations of NF2 and CDKN2A. The genetic and biochemical mechanisms by which BAP1 mutations predispose to MM and how BAP1 interacts genetically with CDKN2A and NF2 to influence MM pathology and therapeutic response are largely unknown. Genetically engineered mouse models can be extremely useful in advancing the understanding tumor development. Previous in vivo carcinogenicity studies of crocidolite, asbestos of the amphibole type, have revealed that mouse models with heterozygous mutations (+/mut) of either Nf2 or Cdkn2a exhibit accelerated induction of MM compared to wild-type (+/+) mice. Moreover, crocidolite- exposed mice with mutations of both Nf2 and Cdkn2a (Nf2+/mut;Cdkn2a+/mut) showed further acceleration of MM induction and a more aggressive tumor phenotype, strongly supporting the notion that inactivation of multiple tumor suppressor genes can cooperate to drive MM pathogenesis. However, whether specific epigenetic alterations are also required for MM development is ill-defined. Moreover, whether Nf2+/mut;Cdkn2a+/mut mice are similarly vulnerable to other forms of asbestos, such as tremolite or chrysotile, and whether Bap1+/mut mice are predisposed to the effects of asbestos, are currently unknown. Additionally, whether biological remediation of asbestos abolishes its carcinogenicity in vivo has not been formally tested in such relevant mouse models of MM. The Testa and Simmons Labs have joined forces to pursue the following Specific Aims: 1) Use a direct in vivo genetic approach to determine if both Bap1+/mut mice and Nf2+/mut;Cdkn2a+/mut mice are predisposed to the induction of MM by both tremolite and chrysotile. 2) Use Nf2+/mut;Cdkn2a+/mut mice to ascertain whether remediation of asbestos suppresses its carcinogenic potential. 3) Identify genome-wide epigenetic modifications resulting in changes in expression, which in turn are associated with MM formation and progression. The proposed studies by two Co-PIs with complementary expertise in genetics and epigenetics represent a comprehensive approach to yield novel basic insights into asbestos carcinogenicity and mechanisms that drive MM development and dissemination, with translational implications for understanding tumor susceptibility and prevention.

Public Health Relevance

The use of genetically engineered mouse models can be extremely useful in advancing the understanding of genetic and biochemical mechanisms by which alterations of certain cancer genes influence the susceptibility and progression of malignant mesothelioma, a cancer caused by exposure to asbestos. Mice with mutations of genes previously implicated in human mesothelioma will be used to assess the carcinogenicity of two different forms of asbestos found at a Superfund site in Ambler, PA and many other parts of the world, and to determine if biological remediation of asbestos abolishes its carcinogenic potential. We will also identify genome-wide epigenetic modifications resulting in changes in expression, which in turn are associated with mesothelioma development, and with translational implications for understanding tumor susceptibility, prevention, and therapeutic response.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
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University of Pennsylvania
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