IDENTIFYING GERMLINE GENES AS TARGETS FOR THERAPEUTIC INTERVENTION IN CANCER

确定种系基因作为癌症治疗干预的目标

• 批准号: 8445954
• 负责人: MARY LOU KING
• 金额: $ 15.3万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-27 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445954
• 关键词: Antineoplastic Agents; Apoptosis; Area; Balbiani Body; Behavior; Biochemical; Biological; Biological Assay; Brain; Cadherins; Cancer Biology; Cancer cell line; Categories; Cell Cycle; Cell Death; Cell Lineage; Cell division; Cell-Cell Adhesion; Cellular Structures; Characteristics; Data; Development; Drosophila genus; Embryo; Epithelial; Gene Expression; Genes; Genetic; Germ; Germ Cell Cancers; Germ Cells; Goals; Immunity; Liquid Chromatography; Malignant Neoplasms; Mesenchymal; Mitochondria; Neoplasm Metastasis; Oocytes; Oogenesis; Organism; Outcome; Process; Proteins; RNA; RNA Sequence Analysis; Research; Screening procedure; Seminal; Source; Specific qualifier value; Structure; Technology; Testing; Therapeutic Intervention; To specify; Tumor Suppressor Genes; Vertebrates; Work; Xenopus; anticancer research; base; cancer stem cell; cancer therapy; drug development; expression cloning; gene function; neuronal cell body; novel; novel marker; scaffold; stem cell biology; tandem mass spectrometry; therapeutic target; tumor; tumor growth

DESCRIPTION (provided by applicant): Recent progress in cancer research has highlighted a new category of targets for anti-cancer drugs: gene products expressed in the germline (Janic et al., 2010; Georlette et al., 2007; Wu and Ruvkun, 2010; Liu et al., 2011; Strumane et al., 2006; Caballero et al., 2009). Seminal work in Drosophila has shown that loss of a tumor suppressor gene causes brain malignancies that display a soma-to-germline transformation with 25% of up-regulated genes having a germline-associated function (Janic et al., 2010). Many of these tumor up-regulated genes are of maternal origin. Importantly, blocking the expression of these genes suppressed tumor growth. Germ cells share at least three important characteristics of cancer, the ability to: sustain a proliferative state, resist cell death, and undergo an epithelial-mesenchymal transition characteristic of invasion and metastasis. These findings strongly support the value of screening germ cell components for their ability to promote these behaviors as a step towards identifying potent therapeutic targets for cancer treatments. However, previous work on identifying germline components has relied almost entirely on RNA microarray data while the proteins remain largely unknown and the majority of RNAs uncharacterized, slowing progress in this area (Yatsu et al., 2008; Molyneaux et al., 2004; Ewen and Koopman, 2010). Germ plasm is the subcellular domain unique to germ cell precursors that contains all the determinants required to specify the germ cell lineage in diverse organisms. Our central hypothesis is that germ plasm will provide a rich source of new targets for anti-cancer drugs. Unfortunately, it is technically difficult to isolate germ plasm in sufficient quantities for proten analysis and thus, genetic information in vertebrates has been limited. Xenopus offers a unique opportunity to isolate biochemical quantities of germ plasm, making it possible, with current technology, to create a complete "parts list" of this cellular "machine" that specifies the totipotnt germ cell lineage. Moreover, Xenopus is highly amenable to expression cloning, allowing a high-throughput approach to assess gene function of germ plasm components. To test our central hypothesis, we will complete the following two specific aims: Aim 1. Identify the protein and RNA components of germ plasm and use this information to predict gene networks operating in the germline and up-regulated in cancer cell lines. Aim 2. Test these germ cell components for their ability to promote the biological "hallmarks" of cancer: metastasis, immortality, and proliferation in bioassays. In preliminary studies, we have isolated biochemical amounts of germ plasm and have identified over 400 proteins by Liquid Chromatography-tandem Mass Spectrometry analyses. We are now ready to launch into broader studies functionally screening germ plasm components for their possible relevance to cancer biology. PUBLIC HEALTH RELEVANCE: Recent progress in cancer research has highlighted a new category of targets for anti-cancer drugs: gene products expressed in the germline. Our proposed research will identify and functionally screen such high value germline targets for their ability to promote the "hallmarks" of cancer: uncontrolled cell division, immunity to cell death, and metastasis. Our research will discover novel candidates for the development of new anti-cancer drugs.

描述（由申请人提供）：癌症研究的最新进展突出了抗癌药物的一类新靶标：在种系中表达的基因产物（Janic et al.，2010; Georlette等人，2007; Wu和Ruvkun，2010; Liu等人，2011; Strumane等人，2006; Caballero等人，2009年）。果蝇中的精液工作已经表明，肿瘤抑制基因的缺失导致脑恶性肿瘤，其显示体细胞到种系的转化，其中25%的上调基因具有种系相关功能（Janic et al.，2010年）。这些肿瘤上调基因中的许多是母体来源的。重要的是，阻断这些基因的表达抑制了肿瘤的生长。生殖细胞具有至少三个癌症的重要特征，即维持增殖状态、抵抗细胞死亡和经历侵袭和转移的上皮-间充质转化特征的能力。这些发现强烈支持筛选生殖细胞组分促进这些行为的能力的价值，作为确定癌症治疗的有效治疗靶点的一步。然而，先前关于鉴定生殖系组分的工作几乎完全依赖于RNA微阵列数据，而蛋白质在很大程度上仍然未知并且大多数RNA未表征，这减缓了该领域的进展（Yatsu et al. 2008; Molyneaux等人，2004; Ewen和Koopman，2010）。种质是生殖细胞前体所特有的亚细胞结构域，它包含了各种生物体中指定生殖细胞谱系所需的所有决定因素。我们的中心假设是，种质将为抗癌药物提供丰富的新靶点来源。遗憾的是，从技术上难以分离足够数量的种质用于蛋白质分析，因此脊椎动物的遗传信息有限。非洲爪蟾提供了一个独特的机会，分离生化量的种质，使之成为可能，与目前的技术，以创建一个完整的“零件清单”的细胞“机器”，指定的totipotnt生殖细胞谱系。此外，非洲爪蟾是非常适合表达克隆，允许高通量的方法来评估种质成分的基因功能。为了检验我们的中心假设，我们将完成以下两个具体目标：目标1。确定生殖质的蛋白质和RNA组分，并使用这些信息来预测在生殖系中运行并在癌细胞系中上调的基因网络。目标2.测试这些生殖细胞成分促进癌症生物学“标志”的能力：转移，永生和生物测定中的增殖。在初步研究中，我们已经分离出生化量的种质，并通过液相色谱-串联质谱分析确定了400多种蛋白质。我们现在准备开展更广泛的研究，从功能上筛选种质成分，以确定它们与癌症生物学的可能相关性。 公共卫生关系：癌症研究的最新进展突出了抗癌药物的一类新靶点：在生殖系中表达的基因产物。我们提出的研究将识别和功能筛选这些高价值的生殖系靶点，以确定它们促进癌症“标志”的能力：不受控制的细胞分裂，对细胞死亡的免疫力和转移。我们的研究将为开发新的抗癌药物发现新的候选药物。