Mechanisms of Adenoid Cystic Carcinoma Development and Tumor Maintenance

腺样囊性癌发生和肿瘤维持的机制

• 批准号: 9708228
• 负责人: CARLOS CAULIN
• 金额: $ 21.49万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9708228
• 关键词: 1p36; Address; Adenoid Cystic Carcinoma; Affect; Alleles; Biological; Biology; Cell Line; Development; Diagnosis; Disease; Distant Metastasis; Epigenetic Process; Experimental Models; Frameshift Mutation; Frequencies; Gene Fusion; Generations; Genes; Genetic; Genetically Engineered Mouse; Goals; Growth; Histologic; Human; Human Biology; Immunotherapy; Length; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Modeling; Molecular; Mus; Mutate; Mutation; NFIB gene; NOTCH1 gene; Nature; Neoplasm Metastasis; Oncogenes; Oncogenic; Pathway interactions; Patients; Proteins; Protocols documentation; Recurrence; Reporting; Role; Salivary; Salivary Glands; Signal Transduction; Stem cells; System; Testing; Tetracyclines; Tissues; Transcription Repressor/Corepressor; Transgenes; Transgenic Mice; Treatment Efficacy; Tumor Suppressor Proteins; Variant; cell stroma; chromosome loss; design; effective therapy; human disease; in vivo; loss of function; mouse model; neoplastic cell; new therapeutic target; notch protein; novel therapeutics; outcome forecast; overexpression; perineural; preclinical study; recombinase-mediated cassette exchange; salivary cell; targeted cancer therapy; therapy design; tool; transcriptome; tumor; tumor growth

PROJECT SUMMARY Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands. Over 60% of the ACC patients succumb to the disease within 15 years from diagnosis. The lack of reliable experimental models for ACC has limited our progress in understanding the biology of the disease and the proliferation of preclinical studies to test new therapies. In this proposal we address this fundamental need by proposing the generation of genetically engineered mouse models that develop autochthonous ACCs. These mice will help determine the role of molecular alterations frequently found in human ACCs and will generate an in vivo platform for molecular and preclinical studies that will help advance towards more effective therapies to treat ACC patients. MYB is by far the most commonly altered gene in human ACCs, as over 70% of the tumors overexpress MYB-NFIB fusions or the full-length MYB. Our preliminary studies show that MYB overexpression in transgenic mice induces ACCs with long latency, indicating that MYB promotes ACC development, but also suggesting that additional alterations are required for ACC development. Genetic alterations affecting MYB-unrelated genes are found at lower frequencies in human ACCs. Notably, mutations in different genes that are predicted to result in activation of NOTCH signaling, including activating mutations in NOTCH1, were found in 25%-35% of the human ACCs, associated with poor prognosis. Of those, inactivating mutations in the SPEN gene were found in ~20% of the ACCs. SPEN is a transcriptional repressor of NOTCH signaling and functions as a tumor suppressor through NOTCH-dependent and NOTCH-independent mechanisms. Importantly, these mutations co-exist with MYB alterations, but their contribution to ACC development is presently unknown. In this proposal we will analyze the cooperation of MYB with NOTCH activation or SPEN inactivation during ACC development, in mouse models that allow the activation of mutations in salivary glands. The inducible nature of the system used to activate these alterations will allow us to determine whether they are required to maintain tumor growth and to identify mechanisms involved in tumor regression. Analysis of the transcriptomes of the tumors that develop in these mice will allow us to identify MYB-regulated genes and pathways that contribute to ACC development, some of which may be required to maintain tumor growth, and thus could be excellent targets to explore new therapies for ACC.

项目摘要 腺样囊性癌是第二常见的涎腺恶性肿瘤。的60%以上 ACC患者在诊断后15年内死于该病。缺乏可靠的实验模型 因为ACC限制了我们在理解疾病生物学和临床前增殖方面的进展， 测试新疗法的研究。在本提案中，我们通过建议生成 开发本地ACC的基因工程小鼠模型。这些老鼠将有助于确定 在人类ACC中经常发现的分子改变，并将产生一个体内分子平台， 和临床前研究，这将有助于推进更有效的治疗ACC患者的疗法。MYB是由 这是人类ACC中最常见的改变基因，因为超过70%的肿瘤过度表达MYB-NFIB融合蛋白 或者全长MYB我们的初步研究表明，转基因小鼠中MYB的过表达诱导ACCs 长潜伏期，表明MYB促进ACC的发展，但也表明，额外的 需要对ACC开发进行修改。影响MYB无关基因的遗传改变被发现于 人类ACC中的频率较低。值得注意的是，不同基因的突变被预测会导致激活 在25%-35%的人ACC中发现了NOTCH信号传导的突变，包括NOTCH 1中的激活突变， 与预后不良有关。其中，SPEN基因的失活突变在约20%的人中被发现。 ACC。SPEN是NOTCH信号传导的转录抑制因子，通过以下途径发挥肿瘤抑制因子的作用： NOTCH依赖性和非依赖性机制。重要的是，这些突变与MYB共存 改变，但其对ACC发育的贡献目前尚不清楚。在这篇文章中，我们将分析 在小鼠模型中，在ACC发育过程中MYB与NOTCH激活或SPEN失活的合作 从而激活唾液腺中的突变用于激活这些细胞的系统的诱导性质 这些改变将使我们能够确定它们是否是维持肿瘤生长所必需的， 参与肿瘤消退的机制。对这些肿瘤的转录组进行分析， 小鼠将使我们能够确定MYB调节的基因和途径，有助于ACC的发展，一些 这可能是维持肿瘤生长所需的，因此可能是探索新疗法的绝佳靶点 对于ACC。