Sunday, December 22, 2024
12/22/2024
PROJECT SUMMARY/ABSTRACT Malignant Mesothelioma (MM), particularly the pleural form of this disease, is a treatment-resistant, rapidly fatal cancer of serosal cells lining the internal body cavities. Exposure to asbestos is causally associated with the development of MM, and asbestos-induced inflammation is a major contributing factor in this process. In some families, heterozygous germline mutations in certain cancer-related genes, especially BAP1, predispose to MM, and mouse models carrying Bap1 mutations have enhanced susceptibility to the carcinogenic effects of asbestos. Moreover, somatic BAP1 mutations/deletions occur in 50-60% of human MM specimens. Our recent whole genome sequencing study of MM patients with a family history of cancer uncovered two families with germline mutations in the Parkinson’s susceptibility gene LRRK2, including a truncating mutation in one family in which 6 siblings developed pleural MM. We later found loss of LRRK2 protein expression in 61% of primary pleural MPMs and MPM cell lines from unrelated individuals. LRRK2 has been linked with various cellular pathways, one of which (NFAT signaling) is implicated in inflammation/immune response and carcinogenesis. Our broad, long-term objective is to determine if LRRK2 loss contributes to MM formation and progression, in part, by dysregulating NFAT, and whether targeting this pathway would have significant therapeutic benefits. In this project, we propose to test whether LRRK2-mediated interactions with NFAT play a key role in asbestos- induced inflammation and MM tumorigenesis. Our hypothesis is that LRRK2 acts as a tumor suppressor gene in MM, that loss of LRRK2 expression contributes significantly to MM pathogenesis, and that future therapeutic approaches exploiting functional attributes associated with LRRK2 loss can lead to improved clinical outcomes in this disease. Overall, this project seeks to elucidate mechanisms by which inactivation of LRRK2 contributes to asbestos carcinogenesis and MM development using a combination of cell biological and in vivo approaches. We propose the following Specific Aims: 1) Does LRRK2 loss promote asbestos-induced tumorigenesis? We will determine if Lrrk2-deficient mice are predisposed to the carcinogenic effects of asbestos, as demonstrated by accelerated asbestos-induced MM development compared to wild-type (WT) littermates. Additionally, we will ascertain if the immune tumor microenvironment differs between MMs from Lrrk2-deficient mice and MMs from WT mice, and if a comparable difference occurs in human MPM. 2) Does LRRK2 loss enhance NFAT-driven inflammatory signaling? Asbestos is thought to contribute to MPM development by inducing inflammation, and we propose to test whether LRRK2 suppresses such inflammation by dampening activity of the transcription factor NFAT. LRRK2 has been shown to bind to the NRON complex, blocking transport of NFAT from the cytosol to the nucleus when cells are in a resting state. Loss of LRRK2 will therefore be expected to cause NFAT to be translocated to the nucleus to mediate transcription. Here we will test if this mechanism may explain how LRRK2 loss may potentiate asbestos-induced inflammation and MM tumorigenesis.
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