Systems analysis of phenotypic switch in control of cancer invasion

项目摘要/摘要：总体 超过90%的癌症相关死亡与癌细胞的侵袭和转移有关 原发肿瘤。在特别具有侵略性的高级别病例中，这种传播可能会灾难性地迅速 黑色素瘤和胶质瘤(即多形性胶质母细胞瘤(GBM))，导致普遍预后不良和短期 这些癌症患者的预期寿命。尽管浸润性癌表型至关重要，但我们仍然有 对导致从增殖性向 癌细胞的侵袭性、迁移性行为(这里称为P-A表型转换)。渐增 有证据表明，这种转变反映了癌细胞采用增殖剂的固有能力。 和Migrator表型，控制在这两个表型之间切换的概率和速度 由细胞基因组、环境条件和细胞-细胞相互作用决定。要解决监管的问题 侵袭性癌症扩散，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)该中心将基于现有的组织和 耶鲁大学西校区最近成立的耶鲁系统生物学研究所(YSBI)的基础设施， 利用现有的大量共享资源，并在同一时间内并置实验室 经过翻新，拥有最先进的研究空间。该中心将汇集来自耶鲁大学7个系的研究人员 总部设在耶鲁大学文理学院、工程学院、应用科学学院和埃默里医学院 耶鲁大学，与耶鲁癌症研究所(与耶鲁大学毗邻)，耶鲁癌症中心， 耶鲁大学皮肤癌孢子学和耶鲁大学神经外科。拟建中心的工作最初将是 根据拟议的紧密结合的两个研究项目和两个支助共享资源核心，初步 重点分析了胶质母细胞瘤和黑色素瘤细胞，以及各种正常细胞的建模 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，扩大范围和目标。拟议的研究已经反映了 YSBI和协作实验室内的参与实验室开展的工作的多样性和创新性， 随着各种技术和方法的结合，如合成生物学、纳米尺度 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、 所有这些都结合到一个综合研究计划中。这项工作将由行政核心和 成果通过外联和教育核心协调的各种机制传播。这个 提出的正交化和非常规化方法的应用和特点 协作使用尖端、创新的方法，其中许多方法是在这里开创的，将提供 一个促进我们对控制侵袭性、侵袭性癌症的分子网络的理解的机会 传播并导致控制和治疗高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.