Systems analysis of phenotypic switch in control of cancer invasion

项目总结/摘要：总体 超过90%的癌症相关死亡率与癌细胞的侵袭性和转移性扩散有关， 原发性肿瘤在特别具有侵略性、高等级的情况下，这种传播可能是灾难性的快。 黑素瘤和神经胶质瘤（即，多形性胶质母细胞瘤（GBM）），导致一致的不良预后和短期 这些癌症的预期寿命。尽管侵袭性癌症表型至关重要，但我们仍然有 只有零碎的知识和了解的机制，导致过渡从增殖， 癌细胞的侵袭性、迁移行为（在此称为P-A表型转换）。增加 有证据表明，这种转换反映了癌细胞的固有能力， 和迁移者表型，控制这两种表型之间转换的概率和速率 由细胞基因组、环境条件和细胞间相互作用决定。为了解决监管问题， 浸润性癌症扩散，更具体地说，P-A表型转换，我们建议建立耶鲁大学 癌症系统生物学中心（Y-CSBC）。中心将在现有组织机构的基础上， 最近在耶鲁西校区成立的耶鲁系统生物学研究所（YSBI）的基础设施， 利用广泛的现有共享资源和最近在同一实验室内的并列 经过翻新的最先进的研究空间该中心将汇集来自耶鲁大学7个系的研究人员 位于耶鲁大学艺术与科学学院、工程与应用科学学院、医学院和埃默里大学 大学与耶鲁癌症研究所（与YSBI相邻）、耶鲁癌症中心密切合作， 耶鲁皮肤癌孢子，耶鲁神经外科。拟建中心的工作将初步 根据拟议的两个研究项目和两个支持共享资源核心， 重点分析了胶质母细胞瘤和黑色素瘤细胞，以及正常细胞的各种种属建模 侵入性生长行为和表型转换。随着时间的推移，对这两种癌症的重视可能会 随着新成员的加入而扩大范围和目标。拟议的研究已经反映了 YSBI和合作实验室内参与实验室所追求的工作的多样性和创新性， 随着合成生物学等多种技术和方法的结合， 生物工程，进化生物学，高通量基因组学，数学建模，新型动物模型， 所有这些都结合成一个综合研究项目。这项工作将得到行政核心的支持， 通过外联和教育核心协调的各种机制传播成果。的 正交和非常规的方法提出的应用和特点的高度 合作使用尖端的创新方法，其中许多方法是在这里开创的，将提供 这是一个机会，可以促进我们对控制侵袭性、侵袭性癌症的分子网络的理解， 传播并导致控制和治疗高度侵袭性和转移性恶性肿瘤的新方法。

PROJECT SUMMARY/ABSTRACT: Overall Over 90% of cancer related mortality is linked to invasive and metastatic spread of cancer cells from the primary tumor. This spread can be catastrophically fast in the cases of particularly aggressive, high grade melanomas and gliomas (i.e., glioblastoma multiforme (GBM)), leading to uniformly poor prognosis and short life expectancy in these cancers. In spite of the crucial importance of invasive cancer phenotype, we still have only fragmentary knowledge and understanding of the mechanisms leading to transition from proliferative to aggressive, migratory behavior of cancer cells (referred here as the P-A phenotypic switch). Increasing evidence suggests that this switch is a reflection of inherent capacity of cancer cells to adopt both proliferative and migrator phenotypes, with the probability and rate of switching between these two phenotypes controlled by the cell genome, environmental conditions and cell-cell interactions. To address the problem of regulation of invasive cancer spread and, more specifically the P-A phenotypic switch, we propose to establish the Yale Cancer Systems Biology Center (Y-CSBC). The Center will based on the existing organization and infrastructure of the recently founded Yale Systems Biology Institute (YSBI) on the Yale West Campus, leveraging the extensive existing shared resources and juxtaposition of the labs within the same recently renovated, state of the art research space. The Center will bring together researchers from 7 Yale departments based at Yale schools of Arts and Science, Engineering and Applied Science and Medicine and Emory University, in close collaboration with Yale Cancer Institute (physically adjacent to YSBI), Yale Cancer Center, Yale skin cancer SPORE, and Yale Neurosurgery department. The work at the proposed Center will be initially based on the Proposed tightly knit two Research Projects and two support shared resource Cores, initially focused on the analysis of glioblastoma and melanoma cells, and normal cells of various species modeling invasive growth behavior and phenotypic switching. With time, the emphasis on these two cancers may broaden with new members expanding the scope and the aims. The proposed research already reflects the diversity and innovative nature of the work pursued by the participating labs within YSBI and collaborative labs, with the combination of techniques and approaches as diverse as synthetic biology, nano-scale bioengineering, evolutionary biology, high throughput genomics, mathematical modeling, novel animal models, all combined into a integrated research program. The work will be supported by the Administrative Core and the results disseminated through various mechanisms mediated by the Outreach and Education Core. The orthogonal and unconventional approaches proposed in the application and characteristic of the highly collaborative use of cutting edge, innovative approaches, many of which are being pioneered here, will provide an opportunity to advance our understanding of the molecular networks controlling invasive, aggressive cancer spread and lead to new approaches to controlling and treating highly invasive and metastatic malignancies.