Brain Cancer Stem Cell Reprogramming by c-Met

描述(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瘤，平均中位生存期仅为15个月。迫切需要新的有效疗法。基底膜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损伤剂的相对抵抗力，以及它们在实验动物中高效繁殖肿瘤异种移植的能力。基底膜干细胞被认为是基底膜对当前治疗方法产生抵抗的原因。这项建议的长期目标是了解支持GBM干细胞的机制，因为治疗GBM的进展很可能取决于针对这些机制。Sox2、Oct4和Nanog等特异性转录因子在维持正常神经干细胞的干性和增殖能力方面具有重要作用。此外，强迫表达这些和其他转录因子(如c-Myc、KLF4)可以诱导或重新编程体细胞成为多能干细胞(IPS)。IPS细胞和GBM SCs的相似性表明，我们的假设是干细胞重新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。这一假说特别得到了将致癌c-Met信号与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支持。这项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启动肿瘤的GBM SCs池。目的研究初诊和复发GBM中干细胞表型、重编程转铁蛋白表达和c-Met的时空关系。目的#2确定Oct4和Nanog在c-Met诱导GBM细胞干化中的作用。目的#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，并且具有临床意义。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启动肿瘤的干细胞表型之间以前未知的联系。这些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的药物抑制剂和其他致癌重编程途径提供有价值的信息。

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.