Mechanisms and Consequences of NOTCH Dysfunction in Head and Neck Cancer

头颈癌中 NOTCH 功能障碍的机制和后果

• 批准号: 8816979
• 负责人: MITCHELL J. FREDERICK
• 金额: $ 40万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816979
• 关键词: Adhesions; Area; Biological; Cancer Etiology; Cancer Patient; Candidate Disease Gene; Cell Adhesion; Cell Line; Cell-Cell Adhesion; Cells; Cessation of life; Clinical; Complex; DNA Sequence Alteration; Data; Disease; Esophagus; Functional disorder; Future; Genes; Genetic; Genetically Engineered Mouse; Genomics; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Hyperplasia; Immunohistochemistry; In Vitro; Integrins; Ions; Knock-out; Knowledge; Lead; Link; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Molecular; Mouse Cell Line; Mus; Mutate; Mutation; NOTCH1 gene; Neoplasm Metastasis; Oncogenes; Oral; Oral cavity; Outcome; Pathway interactions; Patients; Phenotype; Phosphotransferases; Primary Neoplasm; Property; Proteins; Proto-Oncogenes; Publishing; Reporting; Role; Signal Pathway; Signal Transduction; Skin; Solid Neoplasm; Specimen; Squamous Cell Lung Carcinoma; Survival Rate; TP53 gene; Technology; Testing; Tongue; Transgenic Mice; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumorigenicity; Work; base; cancer type; cell motility; clinically significant; cohort; gain of function mutation; in vivo; keratinocyte; leukemia; lymph nodes; malignant mouth neoplasm; malignant phenotype; malignant tongue neoplasm; migration; mouse model; mutant; novel; outcome forecast; overexpression; personalized medicine; programs; public health relevance; receptor; research study; restoration; targeted treatment; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, with roughly 500,000 new cases and 300,000 cancer-related deaths globally occurring each year. Our group has comprehensively characterized the genomic alterations in HNSCC, and we previously reported that NOTCH1 is among the top genes mutated in this disease. The spectrum of NOTCH1 mutations we found suggested the gene is a tumor suppressor in HNSCC, and we recently published experiments which confirmed this by demonstrating restoration of the NOTCH1 gene to HNSCC cell lines with naturally occurring NOTCH1 mutations impairs their growth both in vitro and in vivo. We now have data demonstrating that NOTCH signaling similarly impairs the growth of HNSCC cell lines lacking mutation and expressing wild type NOTCH1 receptors, raising the possibility that this pathway may someday be exploited in a targeted fashion to treat patients with HNSCC. Our preliminary data also show that NOTCH activation in HNSCC lines inhibits cell migration, activates a program of changes in molecules that regulate cell adhesion and adhesion-dependent signaling, and induces genes associated with differentiation and tumor suppression. In addition, we have novel data linking NOTCH reactivation to suppression of proto-oncogenes, a-Catulin and Axl kinase, which have been shown to regulate malignant properties of tumors - suggesting the possibility that loss of these proteins could mediate the tumor suppressive phenotypes in HNSCC induced by NOTCH activation. These observations support a central hypothesis that NOTCH inactivation results in more aggressive tumors because NOTCH activation disrupts adhesion-dependent signaling, causing cells to become more differentiated, lose proliferative capacity, become less migratory or invasive, and upregulate tumor suppressor genes. To test this hypothesis, the cellular and molecular mechanisms by which NOTCH activation inhibits malignant properties will be determined in HNSCC cell lines harboring mutant or wild type NOTCH1 receptors, while the impact of NOTCH mutation on tumor aggressiveness will be studied in genetically-engineered mice and cell lines, and in a clinical patient cohort. Th proposed work should advance our knowledge regarding the biological and clinical significance of the NOTCH pathway in HNSCC, which is critical in order to correctly understand how the pathway may be used for therapy or prognosis in this disease. As inactivating NOTCH1 mutations have now been detected in squamous cell carcinomas from lung and esophagus, knowledge gained from this work could have far reaching implications in our understanding and treatment of solid tumors from multiple types of cancer.

描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)是全球第六大最常见的恶性肿瘤，全球每年约有50万新病例和30万与癌症相关的死亡。我们的团队已经全面描述了HNSCC的基因组变化，我们之前报道过NOTCH1是这种疾病中突变最多的基因之一。我们发现的NOTCH1突变谱表明该基因在HNSCC中是一种肿瘤抑制因子，我们最近发表的实验证实了这一点，通过证明NOTCH1基因恢复到具有自然发生的NOTCH1突变的HNSCC细胞系在体外和体内都会损害它们的生长。我们现在有数据表明，Noch信号类似地损害了缺乏突变和表达野生型NOTCH1受体的HNSCC细胞系的生长，这增加了有朝一日这一途径可能被用于靶向治疗HNSCC患者的可能性。我们的初步数据还显示，HNSCC细胞系中Notch的激活抑制了细胞的迁移，激活了调节细胞黏附和黏附依赖信号的分子变化程序，并诱导了与分化和肿瘤抑制相关的基因。此外，我们有新的数据将缺口重新激活与抑制原癌基因a-Catrin和Axl激酶联系在一起，这两个基因已被证明调节肿瘤的恶性特性--表明这些蛋白的丢失可能介导了缺口激活诱导的HNSCC的肿瘤抑制表型。这些观察结果支持一个中心假设，即缺口失活会导致更具侵袭性的肿瘤，因为缺口激活扰乱了黏附依赖的信号，导致细胞变得更加分化，失去增殖能力，变得不那么迁移或侵袭，并上调肿瘤抑制基因。为了验证这一假设，将在含有突变型或野生型NOTCH1受体的HNSCC细胞系中确定Notch激活抑制恶性特性的细胞和分子机制，同时将在基因工程小鼠和细胞系以及临床患者队列中研究Notch突变对肿瘤侵袭性的影响。这项拟议的工作应该促进我们对HNSCC中Noch通路的生物学和临床意义的了解，这对于正确理解该通路如何用于HNSCC的治疗或预后至关重要。由于目前已在肺癌和食道鳞状细胞癌中检测到NOTCH1失活突变，从这项工作中获得的知识可能对我们理解和治疗多种癌症的实体瘤具有深远的意义。