A Validated Resource of Thyroid Cancer Cell Lines for Pathway Discovery

用于途径发现的经过验证的甲状腺癌细胞系资源

• 批准号: 7943960
• 负责人: JAMES A FAGIN
• 金额: $ 49.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943960
• 关键词: 1-Phosphatidylinositol 3-Kinase; AKT1 gene; Activation Analysis; Address; Advanced Malignant Neoplasm; Antineoplastic Agents; Area; BRAF gene; Back; Bioinformatics; CTNNB1 gene; Cancer Biology; Cancer Patient; Cancer cell line; Cell Line; Cell Survival; Cells; Collaborations; Collection; Colon Carcinoma; Communities; Comparative Study; Computational Biology; Consensus; Core Facility; Critical Pathways; DNA; DNA Fingerprinting; DNA copy number; Data; Databases; Derivation procedure; Development; Diagnosis; Disease; Disease Progression; Distant; Endocrine; Funding; Gene Expression; Generations; Genes; Genetic; Genome; Genomics; Genotype; Histologic; Human; Human Resources; In Vitro; Incidence; Institutes; Life; Link; Literature; Maintenance; Malignant Neoplasms; Malignant neoplasm of thyroid; Mass Spectrum Analysis; Memorial Sloan-Kettering Cancer Center; Metastatic Lesion; Methodology; Mitogen-Activated Protein Kinases; Molecular; Molecular Profiling; Mutation; National Cancer Institute; Neoplasm Metastasis; Occupations; Oncogenes; PIK3CA gene; Pathogenesis; Pathway interactions; Patients; Play; Preparation; Principal Investigator; Procedures; Protein Isoforms; Publications; Qualifying; Refractory; Reporting; Research; Resources; Role; Sampling; Screening procedure; Short Tandem Repeat; Signal Pathway; Signal Transduction; Solid; Solid Neoplasm; Staging; Suppressor Genes; Technology; The University of Colorado Cancer Center; Therapeutic; Thyroid Gland; Time; Tissues; Translational Research; Tumor Suppressor Genes; Tumor Tissue; United States; Wages; Western Blotting; advanced disease; anticancer research; base; cancer cell; cancer genome; effective therapy; experience; genetic profiling; in vivo; melanoma; mortality; new therapeutic target; novel; novel therapeutics; programs; public health relevance; quantum; repository; research study; response; success; symposium; therapeutic target; tool; tumor; working group

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area (15) Translational Science, 15-CA-103: Thyroid Cancer Cell Line Project which is in direct response to our recent discovery showing that 17 out of 40 "thyroid" cancer cell lines are either redundant or misidentified (i.e. of a different tumor lineage including melanoma and colon cancer). The remaining 23 lines are unique and are likely of thyroid origin based on the expression of a limited number of thyroid-specific genes. These cell lines, however, have not been genetically linked to tumors of origin or carefully characterized at a genetic or molecular level. This problem for the research community was reviewed at a recent NCI conference in which the Principal Investigators participated. The need for well- validated thyroid cancer cell lines to study mechanisms of cancer development and progression as well as discovery of novel therapeutic targets was emphasized. In this proposal, we will use three complementary strategies to provide a large panel of comprehensively characterized thyroid cancer cell lines representing primary and metastatic tumors of different histologic types and mutational subtypes (BRAF, RET/PTC, RAS, PIK3CA, AKT1, CTNNB1). We will focus on developing cell lines from poorly differentiated thyroid cancer as well as metastatic lesions that are more likely to harbor mutations that are not represented in the current panel of thyroid cancer cell lines. To establish new cell lines, we will use a parallel in vivo and in vitro approach to maximize our success rate. The new cell lines will be carefully characterized and compared to the corresponding tumor tissue of origin by short tandem repeat (STR) profiling to confirm their derivation. STR profiling and expression of thyroid-specific genes will be used investigate the origins of an additional 36 thyroid cell lines reported in the literature in order to assemble a complete panel of thyroid cancer cell lines. We will use expression arrays of authentic thyroid cancer cell lines to identify a signature that can be used to validate cell lines that have lost expression of thyroid-specific markers or from which patient DNA is unavailable. Finally, we will apply global molecular and genomic approaches with novel computational analyses to the new and existing thyroid cancer cell lines to uncover pathways important in thyroid cancer development and progression. All cell lines, as well as the genomic and gene expression data, will be made available to the research community through a central repository with the assistance of the NCI, and data will be accessible through the NCBI GEO database and UCSC genome browser. Feasibility and Impact: The generation of new cell lines from solid tumors is a challenging task. We propose to generate at least 10 new cell lines in a 12-15 month time period using parallel in vivo and in vitro approaches. There is significant expertise at the University of Colorado Cancer Center (UCCC) with a proven record of success in generating cell lines from solid cancers. We believe that this ambitious proposal is feasible within the two-year time frame because the unique collaboration between the UC Denver and MSKCC has all of these advanced technologies currently in place (new procedures to develop cell lines, gene expression platforms, mass spectrometry genotyping, CGH array analysis, mutational screen of key oncogenes and tumor suppressor genes and high throughput pathway activation analysis by Western blotting). A majority of the sample preparation and studies for the arrays and mutation screening will be performed by experienced personnel in well-equipped cores with rapid turn-around times. Furthermore, we are collaborating with nationally recognized bioinformatics and computational experts to apply novel computational biology strategies to identify important signaling pathways that will better define disease pathogenesis. Successful completion of these aims will provide approximately 40 well-characterized thyroid cancer cell lines for use by the research community to uncover mechanisms of thyroid cancer development, progression, metastatic potential and to serve as a platform for identification of novel therapeutic targets for advanced disease. Lay Summary: Thyroid cancer is the most common endocrine malignancy with an annual incidence of ~34,000. At least 300,000 people are living with a diagnosis of thyroid cancer in the United States, and more than 1,500 of them die each year from this disease. Permanent thyroid cancer cell lines derived from patient's cancers are critical to help us understand the causes of thyroid cancer, how the tumor grows and spreads, and how we can find new ways to treat advanced disease for which there is currently no cure. Recent studies by our research groups have shown that nearly half of the "thyroid" cancer cell lines in current use are not unique and many did not even originate from a thyroid cancer. In order to provide well characterized thyroid cancer cell lines for study by the research community, we will generate new thyroid cancer cell lines that can be linked back to the original tumor tissue. We will also develop approaches by which we can determine whether some of the existing thyroid cancer cell lines are authentic or not. We will develop genetic profiles of all the cancer cell lines, from which we will be able to characterize the abnormal signaling networks that may explain how these cancers develop. Once we know what makes these cancers grow, we will have a better understanding of how to treat them. With the help of the National Cancer Institute, we will make these cell lines widely available to the research community. PUBLIC HEALTH RELEVANCE: The generation of a well-characterized panel of thyroid cancer cell lines has significant relevance for public health as validated tools for the broader research community. Successful completion of the proposed aims will provide approximately 40 well-characterized thyroid cancer cell lines in a central repository for use by the research community to uncover mechanisms of thyroid cancer development, progression, metastatic potential and to serve as a platform for identification of novel therapeutic targets for many types of advanced cancer.

描述（由申请人提供）：该申请涉及广泛的挑战领域（15）转化科学，15-CA-103：甲状腺癌细胞系项目，这是对我们最近发现的直接回应，这表明40个“甲状腺癌细胞”中的17个是多余的或误识的癌细胞线（即，包括不同的tumor领蛋和包括梅兰瘤和结肠癌）。其余23条线是独特的，并且基于有限数量的甲状腺特异性基因的表达，可能是甲状腺起源的。然而，这些细胞系尚未与原始肿瘤相关，或在遗传或分子水平上仔细表征。在最近的NCI会议上审查了研究界的这个问题，主要研究人员参加了该会议。强调了良好的甲状腺癌细胞系来研究癌症发育和进展的机制以及发现新型治疗靶标的机制。在此提案中，我们将使用三种互补策略来提供一大批代表不同组织学类型和突变亚型的原发性和转移性肿瘤（BRAF，RET/PTC，RAS，RAS，PIK3CA，AKT1，CTNNB1）的甲状腺癌细胞系和转移性肿瘤。我们将专注于从分化较差的甲状腺癌以及转移性病变中开发细胞系，这些细胞损伤更可能藏有当前甲状腺癌细胞系中未代表的突变。为了建立新的细胞系，我们将使用平行的体内和体外方法来最大化我们的成功率。新的细胞系将通过短串联重复（STR）分析仔细表征并与相应的原始肿瘤组织进行比较，以确认其推导。将使用甲状腺特异性基因的Str分析和表达，研究文献中报告的另外36个甲状腺细胞系的起源，以组装完整的甲状腺癌细胞系。我们将使用正宗甲状腺癌细胞系的表达阵列来识别可用于验证损失甲状腺特异性标记表达的细胞系的特征，或者无法从中无法获得患者DNA。最后，我们将对新的和现有的甲状腺癌细胞系进行全球分子和基因组方法，以新的计算分析来发现对甲状腺癌发展和进展重要的途径。所有细胞系以及基因组和基因表达数据都将在NCI的帮助下通过中央存储库提供给研究社区，并且可以通过NCBI GEO数据库和UCSC基因组浏览器访问数据。可行性和影响：实体瘤的新细胞系产生是一项艰巨的任务。我们建议使用平行的体内和体外方法在12-15个月的时间内至少生成10个新的细胞系。科罗拉多大学癌症中心（UCCC）具有巨大的专业知识，并在从固体癌症中产生细胞系的成功记录。我们认为，这项雄心勃勃的提议在两年的时间范围内是可行的，因为UC Denver和MSKCC之间的独特合作目前拥有所有这些先进技术（开发细胞系，基因表达平台，质谱基因型，质谱基因型，CGH阵列，CGH阵列分析，关键Oncogen Oncogen和Tumor抑制基因的突变屏幕和高通过PATERTATE分析逐步分析的过程。大多数样本制备和对阵列和突变筛查的研究将由经验丰富的人员进行良好的核心进行，转弯时间很快。此外，我们正在与全国认可的生物信息学和计算专家合作，以应用新颖的计算生物学策略来确定重要的信号通路，以更好地定义疾病发病机理。这些目标的成功完成将提供大约40个特征良好的甲状腺癌细胞系，以供研究界使用，以发现甲状腺癌发展，进展，转移潜力的机制，并用作鉴定新的治疗靶标的晚期疾病的平台。摘要摘要：甲状腺癌是最常见的内分泌恶性肿瘤，年发病率约为34,000。在美国，至少有30万人患有甲状腺癌的诊断，每年有1,500多人死于这种疾病。永久性甲状腺癌细胞系从患者的癌症中得出，这对于帮助我们了解甲状腺癌的原因，肿瘤如何生长和扩散以及我们如何找到治疗当前无法治愈的晚期疾病的新方法至关重要。我们的研究小组的最新研究表明，当前使用中近一半的“甲状腺”癌细胞系并不独特，甚至没有源自甲状腺癌。为了提供良好的甲状腺癌细胞系进行研究社区的研究，我们将产生新的甲状腺癌细胞系，可以将其链接回原始的肿瘤组织。我们还将开发方法，通过这些方法，我们可以确定一些现有的甲状腺癌细胞系是否真实。我们将开发所有癌细胞系的遗传特征，我们将能够从中表征异常的信号网络，这些信号网络可能解释了这些癌症的发展方式。一旦我们知道这些癌症的成长，我们将对如何治疗它们有更好的了解。在国家癌症研究所的帮助下，我们将向研究社区广泛使用这些细胞系。 公共卫生相关性：甲状腺癌细胞系的特征良好的小组的产生与公共卫生具有很大的相关性，作为经过验证的更广泛的研究社区的工具。成功完成所提出的目标将在中央存储库中提供大约40个特征良好的甲状腺癌细胞系，以供研究界使用，以揭示甲状腺癌的发展，进展，转移性潜力的机制，并作为确定许多类型的晚期癌症的新型治疗靶标的平台。