Mechanisms and Consequences of NOTCH Dysfunction in Head and Neck Cancer

描述（由申请人提供）：头颈部鳞状细胞癌（HNSCC）是全球第六大常见恶性肿瘤，全球每年约有50万例新发病例和30万例癌症相关死亡。我们的研究小组已经全面表征了HNSCC的基因组改变，我们以前报道过NOTCH 1是这种疾病中最常见的突变基因之一。我们发现的NOTCH 1突变谱表明该基因是HNSCC中的肿瘤抑制因子，我们最近发表的实验证实了这一点，证明了将NOTCH 1基因恢复到具有天然存在的NOTCH 1突变的HNSCC细胞系中会损害它们在体外和体内的生长。我们现在有数据表明，NOTCH信号传导类似地损害缺乏突变和表达野生型NOTCH 1受体的HNSCC细胞系的生长，提高了这种途径有朝一日可能以靶向方式用于治疗HNSCC患者的可能性。我们的初步数据还表明，NOTCH激活HNSCC细胞系抑制细胞迁移，激活一个程序的分子，调节细胞粘附和粘附依赖性信号的变化，并诱导与分化和肿瘤抑制相关的基因。此外，我们有新的数据将NOTCH再激活与原癌基因α-Catulin和Axl激酶的抑制联系起来，这些原癌基因已被证明可调节肿瘤的恶性特性-这表明这些蛋白质的丢失可能介导由NOTCH激活诱导的HNSCC中的肿瘤抑制表型。这些观察结果支持了一个中心假设，即NOTCH失活导致更具侵袭性的肿瘤，因为NOTCH活化破坏了粘附依赖性信号传导，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。为了检验这一假设，将在携带突变型或野生型NOTCH 1受体的HNSCC细胞系中确定NOTCH激活抑制恶性性质的细胞和分子机制，而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。这项工作将促进我们对NOTCH通路在HNSCC中的生物学和临床意义的认识，这对于正确理解该通路如何用于该疾病的治疗或预后至关重要。由于现在已经在肺和食管鳞状细胞癌中检测到失活的NOTCH 1突变，因此从这项工作中获得的知识可能对我们理解和治疗多种类型癌症的实体瘤具有深远的意义。

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.