Brain Cancer Stem Cell Reprogramming by c-Met

c-Met 进行脑癌干细胞重编程

• 批准号: 8464289
• 负责人: John J Laterra
• 金额: $ 34.12万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464289
• 关键词: Address; Animals; Apoptosis; Biology; Brain Neoplasms; Cells; ChIP-on-chip; Clinical; DNA Damage; Data; EGFR inhibition; Excision; Foundations; Gene Expression; Gene Targeting; Genetic Transcription; Glioblastoma; Glioma; Growth; Human; Laboratories; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mesenchymal Stem Cells; Molecular; Mus; Neonatal; Newly Diagnosed; Oncogenic; Pathway interactions; Phenotype; Play; Pluripotent Stem Cells; Property; Publishing; Receptor Protein-Tyrosine Kinases; Recurrence; Relative (related person); Resistance; Role; Signal Pathway; Signal Transduction; Site; Somatic Cell; Stem Cell Development; Stem cells; Testing; Therapeutic; Tumor Cell Line; Tumor Stem Cells; Xenograft procedure; c-myc Genes; cancer cell; cancer stem cell; cancer therapy; clinically relevant; effective therapy; in vivo; inhibitor/antagonist; medulloblastoma; meetings; migration; neoplastic; neoplastic cell; nerve stem cell; novel; novel therapeutics; overexpression; precursor cell; relating to nervous system; research study; stem; stem cell biology; stemness; transcription factor; tumor; tumor growth; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is an almost universally fatal brain tumor with an average median survival of only ~15 months. New effective therapies are desperately needed. Small subpopulations of malignant cells with stem cell-like properties exist in GBM. These neoplastic stem-like cells (GBM SCs) are distinguishable from the majority of tumor cells by their relative resistance to DNA damaging agents, and their ability to efficiently propagate tumor xenografts in experimental animals. GBM SCs are believed to be responsible for GBM resistance to current therapies. The long-term objectives of this proposal are to understand the mechanisms that support GBM SCs since advances in treating GBM will likely depend upon targeting these mechanisms. Specific transcription factors (TFs) such as Sox2, Oct4, and Nanog, have essential roles in maintaining the stemness and proliferation potential of normal neural stem cells. In addition, the forced expression of these and other TFs (e.g. c-Myc, KLF4) can induce or "reprogram" somatic cells into pluripotent stem (iPS) cells. Similarities between iPS cells and GBM SCs suggest our hypothesis that stem cell reprogramming transcription factors and pathways that induce their expression/function play a major role in the formation and/or tumor propagating capacity of GBM SCs. This hypothesis is specifically supported by preliminary data linking oncogenic c-Met signaling to the GBM SC phenotype and the expression of stem cell reprogramming factors. The experiments outlined in this proposal will rigorously examine the c-Met signaling supports the pool of tumor-initiating GBM SCs via transcriptional reprogramming mechanisms. Aim #1 will determine spatial/temporal relationships between the SC phenotype, reprogramming TF expression, and c-Met in newly diagnosed and recurrent GBM. Aim #2 will determine the roles for Oct4 and Nanog in the induction of GBM cell stemness by c-Met. Aim #3 will identify Nanog transcription targets in GBM-CSCs. Aim #4 will determine the effects of in vivo c-Met inhibition on reprogramming mechanisms and GBM cell stemness. These experiments are timely, of high potential impact, and clinically relevant. Positive results will uncover a previously unknown link between stem cell reprogramming mechanisms induced by oncogenic c-Met signaling and the tumor-initiating stem-like phenotype. Results will alter current paradigms regarding neoplastic stem cell biology and provide valuable information for optimizing the clinical development of stem cell targeting brain cancer therapy, and pharmacologic inhibitors of c-Met and other oncogenic reprogramming pathways.

描述（由申请人提供）：胶质母细胞瘤（GBM）是一种几乎普遍致命的脑肿瘤，平均生存期仅为15个月。迫切需要新的有效疗法。在GBM中存在少量具有干细胞样特性的恶性细胞亚群。这些肿瘤干细胞（GBM SCs）与大多数肿瘤细胞的区别在于它们对DNA损伤剂的相对抗性，以及它们在实验动物中有效繁殖肿瘤异种移植物的能力。GBM SCs被认为是GBM对当前治疗产生耐药性的原因。本提案的长期目标是了解支持GBM SCs的机制，因为治疗GBM的进展可能取决于靶向这些机制。特异性转录因子（TFs）如Sox2、Oct4和Nanog在维持正常神经干细胞的干性和增殖潜能方面发挥着重要作用。此外，强迫表达这些和其他tf（如c-Myc， KLF4）可以诱导或“重编程”体细胞成为多能干细胞（iPS）细胞。iPS细胞和GBM SCs之间的相似性支持了我们的假设，即干细胞重编程转录因子和诱导其表达/功能的途径在GBM SCs的形成和/或肿瘤增殖能力中起主要作用。这一假设得到了初步数据的支持，这些数据将致癌的c-Met信号与GBM SC表型和干细胞重编程因子的表达联系起来。本提案中概述的实验将严格检查c-Met信号通过转录重编程机制支持肿瘤启动GBM SCs库。目的1将确定新诊断和复发GBM中SC表型、重编程TF表达和c-Met之间的时空关系。目的2将确定Oct4和Nanog在c-Met诱导GBM细胞干细胞性中的作用。Aim #3将确定GBM-CSCs中的Nanog转录靶点。目的4将确定体内c-Met抑制对重编程机制和GBM细胞干细胞性的影响。这些实验及时，具有高潜在影响，具有临床相关性。阳性结果将揭示由致癌c-Met信号诱导的干细胞重编程机制与肿瘤启动的干细胞样表型之间先前未知的联系。研究结果将改变目前关于肿瘤干细胞生物学的范式，并为优化干细胞靶向脑癌治疗、c-Met药物抑制剂和其他致癌重编程途径的临床开发提供有价值的信息。