Systems analysis of phenotypic switch in control of cancer invasion

表型转换控制癌症侵袭的系统分析

• 批准号: 9186335
• 负责人: Andre Levchenko
• 金额: $ 199.04万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-08 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186335
• 关键词: Address; Adopted; Advanced Malignant Neoplasm; Affect; Animal Model; Applied Research; Arts; Behavior; Biology; Biomedical Engineering; Cancer Control; Cancer Patient; Cell Communication; Cell Proliferation; Cells; Cessation of life; Characteristics; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Development; Drug resistance; Education and Outreach; Engineering; Environment; Epigenetic Process; Epithelial; Genetic; Genome; Genomics; Glioblastoma; Glioma; Goals; Growth; Institutes; Intervention; Knowledge; Lead; Life Expectancy; Link; Malignant Neoplasms; Mediating; Medicine; Melanoma Cell; Mesenchymal; Metabolic; Methods; Modality; Modeling; Molecular; Molecular Analysis; Molecular Target; Mutation; Nature; Normal Cell; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population Dynamics; Prevention; Primary Neoplasm; Probability; Process; Property; Regulation; Research; Research Infrastructure; Research Personnel; Research Project Grants; Resource Sharing; Schools; Science; Signal Transduction; Site; Skin Cancer; Stromal Cells; System; Systems Analysis; Systems Biology; Techniques; Technology; Time; Universities; Work; Yale Cancer Center; base; cancer cell; cancer type; drug development; innovation; interdisciplinary approach; interest; kinase inhibitor; mathematical analysis; mathematical model; melanoma; member; model design; mortality; nanofabrication; nanoscale; neoplastic cell; neurosurgery; novel; novel strategies; novel therapeutics; outcome forecast; programs; synthetic biology; tumor; tumor growth

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.

项目概要/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 原发肿瘤。在特别具有攻击性的高品位情况下，这种传播速度可能是灾难性的。 黑色素瘤和神经胶质瘤（即多形性胶质母细胞瘤 (GBM)），导致预后普遍较差且短期内 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 对导致从增殖型向增殖型转变的机制仅有零碎的知识和理解 癌细胞的侵袭性、迁移行为（此处称为 P-A 表型转换）。增加 有证据表明，这种转变反映了癌细胞采用两种增殖方式的固有能力 和迁移表型，这两种表型之间切换的概率和速率受到控制 受细胞基因组、环境条件和细胞间相互作用的影响。为解决监管问题 侵袭性癌症扩散，更具体地说是 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)。中心将在现有组织架构的基础上 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以及最近在同一实验室内并置的实验室 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七个院系的研究人员 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 大学与耶鲁大学癌症研究所（物理上毗邻 YSBI）、耶鲁大学癌症中心密切合作， 耶鲁大学皮肤癌 SPORE 和耶鲁大学神经外科。拟议中心的工作最初将是 基于提议的紧密结合的两个研究项目和两个支持共享资源核心，最初 专注于胶质母细胞瘤和黑色素瘤细胞的分析，以及各种物种建模的正常细胞 侵袭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增加 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 和合作实验室内的参与实验室所追求的工作的多样性和创新性， 结合合成生物学、纳米尺度等多种技术和方法 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、 所有这些都合并为一个综合研究计划。这项工作将得到行政核心和 结果通过外展和教育核心介导的各种机制传播。这 正交和非常规方法在高度的应用和特点中提出 协作使用尖端的创新方法（其中许多方法是这里首创的）将提供 这是加深我们对控制侵袭性、侵袭性癌症的分子网络的了解的机会 传播并带来控制和治疗高侵袭性和转移性恶性肿瘤的新方法。