Molecular Mechanism and Therapy for Ocular Melanoma

眼部黑色素瘤的分子机制及治疗

• 批准号: 10341047
• 负责人: JOAN HELLER BROWN
• 金额: $ 47.82万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-14 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341047
• 关键词: Address; Adult; Animal Model; CRISPR/Cas technology; Cell Culture Techniques; Cell Line; Cell physiology; Cells; Cessation of life; Common Neoplasm; Cutaneous Melanoma; DNA Sequence Alteration; Eye; Eye Neoplasms; GNAQ gene; Genes; Genetic; Goals; Luciferases; Malignant Neoplasms; Melanoma Cell; Metastatic Neoplasm to the Liver; Modeling; Molecular; Mutate; Mutation; Nature; Neoplasm Metastasis; Nonmetastatic; Ocular Melanoma; Oncoproteins; Pathway interactions; Phosphorylation; Play; Prognosis; Proteins; Recurrence; Role; Specificity; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tumor Suppressor Proteins; Uveal Melanoma; Verteporfin; cancer genetics; cancer genomics; experimental study; gene interaction; genetic analysis; inhibitor; insight; mouse model; mutant; repaired; therapeutic target; tool; tumor growth; tumorigenesis

Abstract Uveal melanoma is the most common ocular tumor in adults. It harbors genetic mutations very different from those seen in cutaneous melanoma. Liver metastasis is common in uveal melanoma and contributes to the very poor prognosis with average survival of several months. Currently there is no treatment for metastatic uveal melanoma. Activating mutations in GNAQ and GNA11 are the most important cancer drivers, as approximately 80% of uveal melanomas have mutations in either GNAQ or GNA11. Our recent studies have shown that the mutant GNAQ/11 potently activates the YAP oncoprotein, which is a key component of the Hippo tumor suppressor pathway. Moreover, the elevated YAP activity is essential for tumor growth of uveal melanoma cells containing an activating mutation in GNAQ/11. Besides GNAQ/11, mutations in BAP1, SF3B1, and EIF1AX are also frequently observed in uveal melanoma in a mutually exclusive manner. However, a mechanistic understanding of these genes in uveal melanoma and their functional interactions are largely unknown. The major goals of this project are to determine the contributions of the genes commonly mutated in uveal melanoma and their functional interaction in promoting tumorigenesis of uveal melanoma. We also aim to characterize and validate potential therapeutic targets and tools for treatment of uveal melanoma.

抽象的 卵巢黑色素瘤是成年人中最常见的眼部肿瘤。它具有遗传突变截然不同的 从皮肤黑色素瘤中看到的那些。肝转移在紫美黑色素瘤中很常见，并有助于 预后非常差，平均生存率为几个月。目前没有转移性紫菜的治疗方法 黑色素瘤。 GNAQ和GNA11中激活突变是最重要的癌症驱动因素，因为大约 80％的紫veal黑色素瘤在GNAQ或GNA11中具有突变。我们最近的研究表明 突变GNAQ/11有效激活YAP癌蛋白，这是河马肿瘤的关键成分 抑制途径。此外，升高的YAP活性对于卵巢黑色素瘤细胞的肿瘤生长至关重要 包含GNAQ/11中的激活突变。除了GNAQ/11，BAP1，SF3B1和EIF1AX中的突变是 同样在卵巢黑色素瘤中经常以互斥的方式观察到。但是，一种机械 对这些基因的理解及其功能相互作用在很大程度上是未知的。这 该项目的主要目标是确定紫veal瘤中通常突变的基因的贡献 以及它们在促进紫美黑色素瘤肿瘤发生中的功能相互作用。我们还旨在表征和 验证潜在的治疗靶标和治疗紫美黑色素瘤的工具。

项目成果

The Hippo pathway in organ development, homeostasis, and regeneration.

• DOI: 10.1016/j.ceb.2017.12.012
• 发表时间: 2017-12
• 期刊: Current opinion in cell biology
• 影响因子: 7.5
• 作者: Fu V;Plouffe SW;Guan KL
• 通讯作者: Guan KL

Co-occurrence of BAP1 and SF3B1 mutations in uveal melanoma induces cellular senescence.

• DOI: 10.1002/1878-0261.13128
• 发表时间: 2022-03
• 期刊: Molecular oncology
• 影响因子: 6.6
• 作者: Yu L;Zhou D;Zhang G;Ren Z;Luo X;Liu P;Plouffe SW;Meng Z;Moroishi T;Li Y;Zhang Y;Brown JH;Liu S;Guan KL
• 通讯作者: Guan KL

Hippo Signaling in Embryogenesis and Development.

• DOI: 10.1016/j.tibs.2020.08.008
• 发表时间: 2021-01
• 期刊: Trends in biochemical sciences
• 影响因子: 13.8
• 作者: Wu Z;Guan KL
• 通讯作者: Guan KL