Elucidating the Consequences of Chromosome 3 Arm Aneuploidies in Squamous Cell Carcinoma

项目总结 非整倍体，即整个染色体或染色体臂的获得或丢失，几乎是癌症的普遍特征。 然而，非整倍体在肿瘤发病机制中的作用在癌症生物学中仍然是一个悬而未决的问题。 鳞状细胞癌(SCCs)，无论是发生在肺、食道还是头颈部，其特征是 非整倍体的特定模式。在许多鳞状细胞癌中，与其他癌症类型不同，癌基因突变较少。 这导致几乎没有可供患者使用的靶向治疗方法。然而，SCC的特征是具有明显的 非整倍体特征。特别是，染色体臂3p在几乎80%的肺鳞状细胞癌中丢失，并获得 染色体臂3Q是这种癌症类型中下一个最常见的事件。我们的初步数据显示这些 两个非整倍体事件在这种肿瘤类型的肿瘤发生中起着重要作用，可能是一种有用的疾病 目标。 这一建议的目的是了解3号染色体臂非整倍体的表型后果。 我们之前已经开发了一种基因组工程方法来删除人类肺中的染色体臂3p。 上皮细胞。用这种方法，我们还分离出了染色体3q获得的等基因细胞系。使用这个 模型系统，在这里我们将探索这些非整倍体事件影响的三个途径：(1)脂质和PI3K 染色体3Q获得的细胞中的信号，(2)缺氧反应和VHL单倍体功能不全 染色体3p缺失；(3)鳞状细胞分化与肿瘤发生。通过确定 在肺细胞中，染色体3p缺失和染色体3q的获得，我们将获得洞察如何具有患者特异性 非整倍体有助于肿瘤的发展。这些研究还可能确定新的治疗靶点 鳞癌的治疗。

PROJECT SUMMARY Aneuploidy, the gain or loss of whole chromosomes or chromosome arms, is a near-universal feature of cancer. However, the role of aneuploidy in tumor pathogenesis remains an unanswered question in cancer biology. Squamous cell carcinomas (SCCs), whether in the lung, esophagus or head and neck, are characterized by specific patterns of aneuploidy. In many SCCs, unlike other cancer types, there are fewer oncogenic mutations identified resulting in few targeted therapies available for patients. However, SCCs are characterized by a distinct aneuploidy profile. In particular, chromosome arm 3p is lost in almost 80% of lung SCCs, with gain of chromosome arm 3q the next most frequent event in this cancer type. Our preliminary data suggest that these two aneuploidy events play an important role in oncogenesis in this tumor type and may be a useful disease target. The goal of this proposal is to understand the phenotypic consequences of chromosome 3 arm aneuploidies. We have previously developed a genome engineering approach to delete chromosome arm 3p in human lung epithelial cells. With this approach, we also isolated isogenic cell lines with chromosome 3q gain. Using this model system, here we will explore three pathways affected by these aneuploidy events: (1) lipid and PI3K signaling in cells with chromosome 3q gain, (2) hypoxia response and VHL haploinsufficiency in cells with chromosome 3p deletion, and (3) squamous differentiation and tumorigenesis. By determining the effect of chromosome 3p deletion and chromosome 3q gain in lung cells, we will gain insights into how a patient-specific aneuploidy contributes to tumor development. These studies may also identify novel therapeutic targets for treatment of SCCs.