Asymmetric Cell Division and Notch Signaling in Lung Cancer Stem Cells

描述（由申请人提供）：肺癌是癌症死亡的主要原因，据估计，2008年美国有超过16万人死于肺癌；因此，对肺肿瘤细胞生物学的研究对于发现治疗该疾病的新靶点至关重要。最近的证据表明，实体瘤只占肺癌干细胞的一小部分，而这些干细胞是肿瘤的主要来源，可能是转移和对治疗产生耐药性的原因。调控肺癌干细胞自我更新和维持肿瘤生长的机制尚不清楚。在最近的实验中，确定了一小部分肺癌细胞不对称地分裂其模板DNA，并且该过程被Notch通路抑制剂所废除。这一发现对正常和肿瘤细胞稳态的研究具有广泛的意义。该建议的中心假设是Notch信号通过维持不对称和对称分裂之间的动态平衡来调节肺癌干细胞库。目的是确定肺癌细胞的不对称分裂是否仅限于癌症干细胞部分，以及Notch信号是否调节肺癌细胞的不对称分裂。实现这些目标的第一个具体目标是研究不对称细胞分裂作为一种仅限于肺CSC池的基本机制。第二个目的是研究典型Notch信号作为肺癌中不对称细胞分裂和CSC自我更新的调节因子。这将通过分析Notch通路基因在不对称分裂的人肺癌细胞中的表达，以及靶向鉴定的蛋白质来破坏不对称细胞分裂和改变自我更新来实现。提出的研究的基本原理是，一旦知道CSC库的自我更新是由控制不对称分裂的机制调节的，这些途径随后可以通过新的和创新的方法在治疗肺癌的药理学上靶向。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death and is estimated to claim over 160,000 lives in the United States in 2008; thus, the study of lung tumor cell biology is critical for discovering novel targets to treat the disease. Recent evidence suggests that solid tumors comprise a small fraction of lung cancer stem cells that seed the tumor bulk and may be responsible for metastases and resistance to therapy. The mechanisms regulating how lung cancer stem cells undergo self-renewal and maintain tumor growth are unknown. In recent experiments, it was determined that a small fraction of lung cancer cells asymmetrically divide their template DNA, and that the process is abrogated by Notch pathway inhibitors. This finding has broad implications in normal and tumor cell homeostasis research. The central hypothesis of this proposal is that Notch signaling regulates the lung cancer stem cell pool by maintaining a dynamic balance between asymmetric and symmetric divisions. The objectives are to determine if asymmetrically dividing lung cancer cells are restricted to the cancer stem cell fraction and if Notch signaling regulates asymmetric cell division in lung cancer. The first specific aim to achieve these objectives is to study asymmetric cell division as a fundamental mechanism restricted to the lung CSC pool. The second aim is to investigate canonical Notch signaling as a regulator of asymmetric cell division and CSC self-renewal in lung cancer. This will be achieved by expression analysis of Notch pathway genes in asymmetrically dividing human lung cancer cells, and targeting of identified proteins for disruption of asymmetric cell division and alterations in self-renewal. The rationale of the proposed research is that, once it is known that self-renewal of the CSC pool is regulated by mechanisms that control asymmetric division, those pathways can later be targeted pharmacologically by new and innovative approaches in the treatment of lung cancer. PUBLIC HEALTH RELEVANCE: Cancer of the lung is the leading cause of cancer deaths in the United States. For several decades, there has been limited improvement in lung cancer survival that is attributed to early detection or targeted therapy, and the five-year survival rate hovers at a meager 15-20%. Studies aimed at unraveling the fundamental properties governing how lung tumors are maintained may lead to novel and more efficacious therapies.