Epigenetic reprogramming of malignant stem cells of the testes

睾丸恶性干细胞的表观遗传重编程

• 批准号: 7458969
• 负责人: MICHAEL J SPINELLA
• 金额: $ 19.19万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458969
• 关键词: 12p; Address; Affect; Area; Attention; Carcinoma; Cell Cycle Arrest; Cell Differentiation process; Cells; Cellular biology; Chromatin; Chromosomes; Clinical; Complex; Disease; Down-Regulation; Embryonal Carcinoma; Embryonal Carcinoma Cell; Epigenetic Process; Gene Expression; Gene Targeting; Genes; Genetic; Germ Cells; Goals; Grant; Histones; Hour; Human; Laboratories; Lead; Link; Localized; Maintenance; Malignant - descriptor; Malignant Conversion; Malignant Neoplasms; Mediating; Modeling; Modification; Molecular; Molecular Genetics; Neurons; Pathway interactions; Polycomb; Publishing; Repression; Resistance; Role; Signal Transduction; Solid Neoplasm; Specimen; Stem cells; Structure of primordial sex cell; System; Testicular Germ Cell Tumor; Testing; Testis; Tretinoin; Tumorigenicity; Variant; base; cancer stem cell; chemotherapy; chromatin remodeling; gene repression; human embryonic stem cell; loss of function; neoplastic cell; pluripotency; programs; self-renewal; tumor; tumorigenic

DESCRIPTION (provided by applicant): Embryonal carcinoma (EC) are the stem cells of testicular germ cell tumors (TGCTs), are pluripotent, and share remarkable genetic and biologic similarity to human ES cells. We contend that EC can be seen as an archetypal model of successfully treated, malignant cancer stem cells. Our efforts to define the molecular mechanisms of retinoic acid (RA) mediated tumor cell differentiation using global gene expression analysis and a unique system of RA-sensitive and RA-resistant human EC has led to our hypothesis that a critical determinant of loss of tumorigenicity of EC is epigenetic reprogramming. This evidence is based in part on a set of candidate pluripotency genes, including a polycomb group gene involved in Hox gene repression, PHC1/EDR1, that we discovered to be rapidly downregulated by RA at the lineage commitment window. We provide evidence that EDR1 and other pluripotency genes may be regulated by RA via RA-mediated downregulation of the master pluripotency factor Oct4. Interestingly, many of these RA-downregulated pluripotency genes reside on chromosome 12p, which is uniformly amplified in TGCTs. Hence, we propose that the malignant conversion of the normal primordial germ cell to the EC cell may involve "enforced" pluripotency with associated chromatin remodeling. The hypothesis to be tested is that RA-induced loss of stem cell renewal is in part due to transcriptional modulation of EDR1 leading to epigenetic reprogramming and lineage commitment of EC cells. The goal of this R21 Stem Cells and Cancer application is to begin to characterize histone modifications in EC cells associated with tumorigenic and curative potential. Our focus is the polycomb complex since alterations in this complex are known to be closely associated with a variety of human cancers and since we have shown that RA downregulates a specific polycomb gene EDR1 that is localized to the critical 12p amplicon in TGCTs. This will be accomplished through molecular, genetic and cell biologic approaches to complete the following specific aims. 1. To define polycomb-specific chromatin modifications of RA-sensitive EC and RA-resistant EC and to determine whether RA is a major morphogenic signal regulating polycomb-specific repression and cancer stem cell renewal. 2. To determine the role of the RR12 gene, EDR1, in RA-mediated, polycomb-specific reprogramming of cancer stem cell renewal in embryonal carcinoma. These studies are important because the unique "germ cell-like" epigenetics of human EC may be linked to the curability of TGCTs. Testicular germ cell tumors (TGCTs) are one of the few solid tumors curable with chemotherapy even when highly advanced, suggesting that the self-renewing, cancer stem cells of TGCTs are likely targeted during therapy. Completion of the aims of this grant will increase understanding of the genetics and biologic progression of TGCTs and may increase understanding of why these tumors are so curable when the vast majority of advanced solid tumors are not. This in turn may lead to new therapies that effectively target crucial cells within tumors, cancer stem cells.

描述（由申请人提供）：胚胎癌（EC）是睾丸生殖细胞肿瘤（TGCT）的干细胞，具有多能，并且与人ES细胞具有显着的遗传和生物学相似性。我们认为，EC可以看作是成功治疗的恶性癌干细胞的原型模型。我们为定义视黄酸（RA）使用全球基因表达分析的肿瘤细胞分化的分子机制和RA敏感和耐RA耐药的人EC的独特系统的努力导致了我们的假设，即EC肿瘤性衰老的关键决定因素是表观遗传重编程。该证据部分基于一组候选多能基因，包括参与HOX基因抑制作用PHC1/EDR1的PolyComb基因，我们发现在谱系承诺窗口中，RA迅速下调了这些基因。我们提供的证据表明，EDR1和其他多能基因可以通过RA介导的主要多能因子OCT4的RA调节。有趣的是，其中许多RA调节的多能基因都位于12p染色体上，该基因在TGCT中均匀扩增。因此，我们提出，正常原始生殖细胞向EC细胞的恶性转化可能涉及与相关的染色质重塑的“强化”多能性。要检验的假设是，RA诱导的干细胞更新丢失部分是由于EDR1的转录调节导致EC细胞的表观遗传重编程和谱系承诺。该R21干细胞和应用癌症的目的是开始表征与致肿瘤和治疗潜力相关的EC细胞中的组蛋白修饰。我们的重点是PolyComb复合物，因为已知该复合物的变化与各种人类癌症密切相关，并且由于我们已经表明RA下调了特定的PolyComb基因EDR1，该基因eDR1位于TGCT中的关键12p Amplicon。这将通过分子，遗传和细胞生物学方法来完成以下特定目标。 1。定义对RA敏感的EC和耐RA的EC的多孔特异性染色质修饰，并确定RA是否是调节多肉液特异性抑制和癌症干细胞更新的主要形态学信号。 2。确定RR12基因EDR1在RA介导的胚胎癌中癌干细胞更新的PolyComb特异性重编程中的作用。这些研究很重要，因为人类EC的独特“生殖细胞样”表观遗传学可能与TGCT的可疗法有关。睾丸生殖细胞肿瘤（TGCTs）是即使高度疗法的少数可以治愈化疗的实体瘤之一，这表明在治疗过程中，自我更新，TGCT的癌症干细胞可能是针对的。该赠款目标的完成将增加对TGCT的遗传学和生物学进展的理解，并可能会增加对这些肿瘤在绝大多数晚期实体肿瘤中如此可治愈的理解。反过来，这可能导致新的疗法有效地靶向肿瘤中的癌症干细胞中的关键细胞。