Role of the Parkinson's susceptibility gene LRRK2 in NFAT-mediated malignant mesothelioma tumorigenesis

帕金森病易感基因 LRRK2 在 NFAT 介导的恶性间皮瘤肿瘤发生中的作用

• 批准号: 10653572
• 负责人: Joseph R. Testa
• 金额: $ 9.4万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653572
• 关键词: Acceleration; Amphiboles; Asbestos; Asbestos-Related Malignant Mesothelioma; Binding; Biological; Biological Markers; Biological Models; CSNK1A1 gene; Calmodulin; Cell Line; Cell Nucleus; Cells; Clinical; Complex; Cytosol; DNA; Development; Disease; Disease Management; Dissociation; Environment; Exposure to; Family; Family Cancer History; Fiber; Future; Genes; Genetic Transcription; Germ-Line Mutation; Goals; Heterozygote; Human; Immune response; Individual; Inflammation; Inflammatory; Interphase Cell; LRRK2 gene; Link; Malignant Neoplasms; Malignant Pleural Mesothelioma; Malignant mesothelioma; Malignant neoplasm of lung; Mediating; Mesothelioma; Molecular Biology; Molecular Conformation; Mus; Mutation; Normal Cell; Nuclear Translocation; Operative Surgical Procedures; Outcome; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Pericardial cavity; Peritoneal; Phosphorylation; Phosphotransferases; Play; Pleural; Precision therapeutics; Predisposition; Process; Protein Dephosphorylation; Public Health; Reactive Oxygen Species; Refractory Disease; Reporting; Resistance; Rest; Risk; Role; Siblings; Signal Pathway; Signal Transduction; Somatic Mutation; Specimen; Stimulus; Susceptibility Gene; Testing; Therapeutic; Thick; Thinness; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; Variant; Wild Type Mouse; body cavity; calcineurin phosphatase; cancer cell; carcinogenesis; carcinogenicity; cell transformation; checkpoint therapy; disorder prevention; gene product; genome sequencing; improved; in vivo; malignant breast neoplasm; mouse model; novel; novel strategies; nuclear factors of activated T-cells; patient stratification; protein expression; response; tumor; tumor-immune system interactions; tumorigenesis; whole genome

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.

项目摘要/摘要 恶性间皮瘤（MM），尤其是这种疾病的胸膜形式，是一种耐药性，迅速致命的 内体腔内衬里的血清细胞癌。暴露于石棉有时与 MM的发展和石棉引起的炎症是此过程的主要促成因素。在某些人中 家族，某些与癌症相关基因的杂合种系突变，尤其是BAP1，易于MM， 携带BAP1突变的小鼠模型对致癌作用的敏感性增强了 石棉。此外，体细胞BAP1突变/缺失发生在50-60％的人类MM标本中。我们最近 对患有癌症家族史的MM患者的全基因组测序研究发现了两个家庭 帕金森易感性基因lrrk2中的种系突变，包括一个家庭的截断突变 其中6个兄弟姐妹出现了胸膜mm。后来我们发现61％的原发性LRRK2蛋白表达丧失 来自无关个体的胸膜MPM和MPM细胞系。 LRRK2已与各种细胞联系在一起 途径（NFAT信号传导）是在炎症/免疫反应和致癌作用中实现的。 我们广泛的长期目标是确定LRRK2损失是否有助于MM形成和进展 部分，通过失调NFAT以及针对此途径是否具有显着的热益处。在 该项目，我们建议测试LRRK2介导的NFAT相互作用是否在石棉中起关键作用 诱导注射和MM肿瘤发生。我们的假设是LRRK2充当肿瘤抑制基因 在MM中，LRRK2表达的丧失对MM发病机理和未来治疗产生了重大贡献。 利用与LRRK2损失相关的功能属性的方法可以改善临床结果 在这种疾病中。总体而言，该项目旨在阐明LRRK2失活的机制 使用细胞生物学和体内方法的组合来进行石棉癌变和MM发育。 我们提出以下特定目的：1）LRRK2损失是否促进石棉诱导的肿瘤发生？我们 将确定LRRK2缺乏小鼠是否倾向于石棉的致癌作用，如证明 与野生型（WT）同窝仔相比，通过加速石棉诱导的MM发育。此外，我们会的 确定免疫肿瘤微环境在LRRK2缺乏小鼠和MMS的MMS之间是否有所不同。 WT小鼠，如果在人MPM中发生可比的差异。 2）LRRK2损失会增强NFAT驱动 炎症信号传导？石棉被认为会通过诱导注射来促进MPM开发，并且 我们建议测试LRRK2是否通过抑制转录活性来抑制这种注射 因子NFAT。 LRRK2已显示与NRON复合物结合，阻断了NFAT从细胞质的转运 当细胞处于静息状态时，到核。因此，LRRK2的损失将有望导致NFAT为 转移到核中介导转录。在这里，我们将测试该机制是否可以解释LRRK2如何 损失可能会导致石棉诱导的感染和MM肿瘤发生。