Brain Cancer Stem Cell Reprogramming by c-Met

描述（由申请人提供）：胶质母细胞瘤（GBM）是一种几乎普遍存在的致命性脑肿瘤，平均中位生存期仅约15个月。迫切需要新的有效疗法。在GBM中存在具有干细胞样性质的恶性细胞的小亚群。这些肿瘤干细胞样细胞（GBM SC）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 SC被认为是GBM对当前疗法的抗性的原因。该提案的长期目标是了解支持GBM SC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（TF）如Sox 2、Oct 4和Nanog在维持正常神经干细胞的干细胞性和增殖潜力方面具有重要作用。此外，这些和其他TF（例如c-Myc、KLF 4）的强制表达可以诱导或“重编程”体细胞成为多能干（iPS）细胞。iPS细胞和GBM SC之间的相似性表明我们的假设，即诱导其表达/功能的干细胞重编程转录因子和途径在GBM SC的形成和/或肿瘤增殖能力中起主要作用。这一假设得到了将致癌c-Met信号传导与GBM SC表型和干细胞重编程因子表达联系起来的初步数据的特别支持。本提案中概述的实验将严格检查c-Met信号传导通过转录重编程机制支持肿瘤起始GBM SC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之间的空间/时间关系。目的#2将确定Oct 4和Nanog在c-Met诱导GBM细胞干细胞性中的作用。目标#3将鉴定GBM-CSC中的Nanog转录靶标。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。这些实验是及时的，具有很高的潜在影响，并且具有临床相关性。阳性结果将揭示致癌c-Met信号诱导的干细胞重编程机制与肿瘤起始干细胞样表型之间的先前未知联系。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的临床开发以及c-Met和其他致癌重编程途径的药理学抑制剂提供有价值的信息。

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.