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.

项目摘要/摘要：总体 超过90％的癌症死亡率与癌细胞的侵入性和转移性有关 原发性肿瘤。在特别侵略性高级的情况下，这种传播可能在灾难性上很快 黑色素瘤和神经胶质瘤（即多形胶质母细胞瘤（GBM）），导致预后均匀差，短 这些癌症的预期寿命。尽管侵入性癌症表型的重要性至关重要，但我们仍然有 只有零碎的知识和对导致从增殖过渡到的机制的理解 癌细胞的侵略性，迁移行为（此处称为P-A表型转换）。增加 有证据表明，这种转换反映了癌细胞既采用既增殖的固有能力 和迁移者表型，这两种表型之间的概率和切换率 通过细胞基因组，环境条件和细胞 - 细胞相互作用。解决监管问题 侵入性癌症扩散，更具体地说是P-A表型开关，我们建议建立耶鲁 癌症系统生物学中心（Y-CSBC）。该中心将根据现有组织以及 最近成立的耶鲁系统生物学研究所（YSBI）的基础设施在耶鲁大学西校园 最近在同一中利用实验室的广泛共享资源和并置 经过翻新，最先进的研究空间。该中心将聚集来自耶鲁7个部门的研究人员 位于耶鲁大学艺术与科学，工程和应用科学与医学与埃默里 大学与耶鲁癌症研究所密切合作（与YSBI的物理相邻），耶鲁癌症中心， 耶鲁大学皮肤癌孢子和耶鲁神经外科部门。最初，拟议中心的工作将是 根据拟议的紧密编织两个研究项目和两个支持共享资源核心，最初 专注于分析胶质母细胞瘤和黑色素瘤细胞，以及各种物种建模的正常细胞 侵入性生长行为和表型切换。随着时间的流逝，对这两种癌症的重视可能 随着新成员扩大范围和目标的扩大。拟议的研究已经反映了 YSBI和协作实验室中参与实验室从事的工作的多样性和创新性质， 与合成生物学一样多样化的技术和方法的结合，纳米级 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， 所有这些都合并为综合研究计划。这项工作将由行政核心和 结果通过外展和教育核心介导的各种机制传播。这 高度应用和特征提出的正交和非常规的方法 尖端的协作使用，创新的方法，其中许多正在启用此处，将提供 一个机会，可以促进我们对控制侵入性，侵略性癌症的分子网络的理解 传播并导致控制和治疗高度侵入性和转移性恶性肿瘤的新方法。