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

阐明鳞状细胞癌中染色体 3 臂非整倍体的后果

• 批准号: 10736206
• 负责人: Alison M. Taylor
• 金额: $ 40.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736206
• 关键词: Adenocarcinoma; Affect; Aneuploidy; Biological Models; Cancer Biology; Cell Line; Cell model; Cells; Chemicals; Chromosome 3; Chromosome Arm; Chromosome Deletion; Chromosome abnormality; Chromosomes; Conventional (Clear Cell) Renal Cell Carcinoma; DNA Sequence Alteration; DNA copy number; Data; Development; Disease; Dose; Epithelial Cells; Esophagus; Event; Exhibits; Future; Gene Deletion; Gene Expression; Genes; Genetic Engineering; Genetic Screening; Genetic Transcription; Genome; Genome engineering; Goals; HIF1A gene; Head and neck structure; Human; Human Characteristics; Hypoxia; Individual; Invaded; Laboratories; Lipids; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Measures; Methods; Mutate; Mutation; Oncogenes; Oncogenic; Organoids; Oxidative Stress; PIK3CA gene; PIK3CG gene; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Phosphatidylinositols; Play; Production; Role; Signal Transduction; Squamous Cell Lung Carcinoma; Squamous Differentiation; Squamous cell carcinoma; System; Tissues; Tumor Suppressor Proteins; VHL gene; arm; cancer cell; cancer diagnosis; cancer type; chromosome 3q gain; experimental study; insight; lipidome; migration; new therapeutic target; novel; precision medicine; pressure; response; stem; targeted treatment; therapeutic target; tool; transcription factor; tumor; tumor progression; tumorigenesis; tumorigenic

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.

项目概要 非整倍性，即整个染色体或染色体臂的获得或丢失，是癌症几乎普遍存在的特征。 然而，非整倍性在肿瘤发病机制中的作用仍然是癌症生物学中尚未解答的问题。 鳞状细胞癌 (SCC)，无论是肺、食道还是头颈癌，其特征是 非整倍体的特定模式。与其他癌症类型不同，许多鳞状细胞癌的致癌突变较少 导致患者可用的靶向治疗很少。然而，SCC 的特点是具有独特的 非整倍体概况。特别是，近 80% 的肺 SCC 中染色体臂 3p 丢失，增加了 染色体臂 3q 是这种癌症类型中下一个最常见的事件。我们的初步数据表明，这些 两个非整倍体事件在该肿瘤类型的肿瘤发生中发挥重要作用，并且可能是一种有用的疾病 目标。 该提案的目标是了解 3 号染色体臂非整倍体的表型后果。 我们之前开发了一种基因组工程方法来删除人肺中的染色体臂3p 上皮细胞。通过这种方法，我们还分离了具有染色体 3q 增益的同基因细胞系。使用这个 模型系统，在这里我们将探讨受这些非整倍性事件影响的三个途径：（1）脂质和PI3K 具有染色体 3q 增益的细胞中的信号转导，(2) 具有染色体 3q 增益的细胞中的缺氧反应和 VHL 单倍体不足 染色体 3p 缺失，以及 (3) 鳞状细胞分化和肿瘤发生。通过确定效果 肺细胞中染色体 3p 缺失和染色体 3q 增加，我们将深入了解患者特异性如何 非整倍性有助于肿瘤的发展。这些研究还可能确定新的治疗靶点 鳞状细胞癌的治疗。