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.

项目概要/摘要 恶性间皮瘤 (MM)，尤其是这种疾病的胸膜形式，是一种难治性、快速致命的疾病 体内腔内衬浆膜细胞的癌症。接触石棉与以下因素有因果关系 MM 的发展，而石棉引起的炎症是这一过程的主要促成因素。在一些 某些癌症相关基因（尤其是 BAP1）的杂合种系突变易患 MM， 携带 Bap1 突变的小鼠模型对致癌作用的敏感性增强 石棉。此外，50-60% 的人类 MM 标本中发生体细胞 BAP1 突变/缺失。我们最近的 对有癌症家族史的多发性骨髓瘤患者的全基因组测序研究发现，两个家族患有癌症 帕金森氏症易感基因 LRRK2 的种系突变，包括一个家族的截短突变 其中 6 名兄弟姐妹患有胸膜 MM。我们后来发现 61% 的原代细胞中 LRRK2 蛋白表达缺失 来自无关个体的胸膜 MPM 和 MPM 细胞系。 LRRK2 已与多种细胞相关 其中之一（NFAT 信号传导）与炎症/免疫反应和致癌作用有关。 我们广泛的长期目标是确定 LRRK2 缺失是否会导致 MM 的形成和进展， 部分是通过 NFAT 失调，以及针对该通路是否会产生显着的治疗益处。在 在这个项目中，我们建议测试 LRRK2 介导的与 NFAT 的相互作用是否在石棉- 诱导炎症和 MM 肿瘤发生。我们的假设是 LRRK2 作为肿瘤抑制基因 在 MM 中，LRRK2 表达缺失对 MM 发病机制有显着影响，未来的治疗 利用与 LRRK2 丢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 结合细胞生物学和体内方法研究石棉致癌和多发性骨髓瘤的发展。 我们提出以下具体目标：1）LRRK2 缺失是否会促进石棉诱导的肿瘤发生？我们 将确定 Lrrk2 缺陷小鼠是否容易受到石棉的致癌作用，如所证明的 与野生型 (WT) 同窝小鼠相比，石棉诱导的 MM 发育加速。此外，我们将 确定 Lrrk2 缺陷小鼠的 MM 和来自 Lrrk2 缺陷小鼠的 MM 之间的免疫肿瘤微环境是否不同 WT 小鼠，以及如果人类 MPM 中出现类似差异。 2) LRRK2 丢失是否增强了 NFAT 驱动 炎症信号传导？石棉被认为通过诱导炎症来促进 MPM 的发展，并且 我们建议测试 LRRK2 是否通过抑制转录活性来抑制这种炎症 因素 NFAT。 LRRK2 已被证明可以与 NRON 复合物结合，阻断 NFAT 从细胞质中的转运 当细胞处于静止状态时，进入细胞核。因此，LRRK2 的丢失预计会导致 NFAT 易位至细胞核以介导转录。在这里我们将测试这个机制是否可以解释LRRK2如何 损失可能会加剧石棉诱发的炎症和多发性骨髓瘤（MM）肿瘤的发生。