Systems Analysis of Stress-adapted Cancer Organelles (SASCO) Center

应激适应癌症细胞器系统分析 (SASCO) 中心

• 批准号: 10703471
• 负责人: Kevin A Janes
• 金额: $ 208.14万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703471
• 关键词: Adopted; Aneuploidy; Automobile Driving; Cancer Biology; Cancer Model; Cell Culture Techniques; Cell membrane; Cells; Cellular biology; Charge; Chromosomes; Chronic; Clinical and Translational Science Awards; Collaborations; Colorectal Cancer; Complex; Couples; Cultured Cells; Data; Decision Making; Dedications; Defect; Disease; Ecosystem; Education; Elements; Epidermal Growth Factor Receptor; Eukaryota; Faculty; Fostering; Genetically Engineered Mouse; Genomics; Glioblastoma; Goals; Growth; Image; Immunofluorescence Immunologic; Indirect Immunofluorescence; Institution; Joints; KRAS2 gene; Lead; Leadership; Length; Lesion; Life; Malignant Neoplasms; Malignant neoplasm of brain; Mentorship; Metabolic; Metaphase; Metastatic Neoplasm to the Liver; Mitochondria; Mitotic; Modeling; Mutation; NCI Center for Cancer Research; Neoplasm Metastasis; Oncogene Activation; Oncogenes; Oncogenic; Organelles; Pathway interactions; Phase; Phenotype; Pilot Projects; Play; Positioning Attribute; Primary Neoplasm; Process; Proliferating; Records; Recurrence; Research; Research Personnel; Research Project Grants; Resolution; Resource Sharing; Resources; Rest; Role; Secondary to; Signal Transduction; Site Visit; Standardization; Stress; Structure; System; Systems Analysis; Systems Biology; Testing; Training; Universities; Virginia; Vision; cancer cell; cancer type; career; cell type; clinical practice; cost; experimental study; feature detection; feature extraction; image registration; innovation; interoperability; learning strategy; malignant breast neoplasm; mitochondrial membrane; multidisciplinary; mutant; outreach; programs; repaired; residence; response; success; summer research; transcription factor; tumor; tumorigenesis; undergraduate research experience

PROJECT SUMMARY/ABSTRACT Oncogene activation is modulated by normal subcellular compartments that execute specialized functions related to hallmark cancer phenotypes. These organelles must adapt to oncogenic stress in order for tumors to initiate and progress, but there is little to no systems-level understanding of how such adaptations occur and what vulnerabilities might be created. The Systems Analysis of Stress-adapted Cancer Organelles (SASCO) Center at the University of Virginia will address this challenge by mechanistic modeling of organellar processes that iterates with quantitative experiments in disease-relevant cell cultures and primary tumors. The working SASCO Center hypothesis is that organelle-specific adaptation to oncogenic stress occurs through a few critical bottlenecks, which become identifiable once the relevant signaling, metabolic, and transport pathways have been properly integrated. The Center brings together 14 investigators with primary and collaborative track records in cancer biology, systems biology, genetically engineered mouse models of cancer, and clinical practice. Three Research Projects and one Shared Research Core will pursue a common research strategy, which leverages mechanistic models to test competing alternative hypotheses about how organelles adapt to stresses from proximal oncogenes that drive specific types of cancer. The Projects are organized hierarchically as organelle stresses downstream of proliferation-inducing oncogenes. Project 1 will examine the chromosome passenger complex and its regulated phase separation during metaphase as an organelle that senses and repairs spindle defects to suppress breast cancer aneuploidy driven by mitotic transcription factors. Project 2 will evaluate the metabolic consequences of chronic mitochondrial fragmentation caused by mutant KRAS in primary colorectal cancers and secondary liver metastases. Project 3 will investigate localized signal-transduction rebalancing as a mechanism for alleviating plasma-membrane stress caused by EGFR amplification in glioblastoma. All Research Projects will rely on the High-Content Imaging & Analysis Core to obtain iterative multichannel immunofluorescence data with organelle-level resolution and quantification. The SASCO Outreach Core amplifies ongoing programs at the University of Virginia to provide summer research experiences for undergraduates and faculty scholars from historically underrepresented backgrounds as well as introductory systems biology modeling materials for clinicians across the Commonwealth of Virginia. The SASCO Center will thus create a national headquarters for subcellular cancer systems biology within the broader Cancer Systems Biology Consortium.

项目概要/摘要 癌基因激活由执行特殊功能的正常亚细胞区室调节 与标志性癌症表型相关。这些细胞器必须适应致癌应激才能产生肿瘤 来启动和进展，但对这种适应如何发生和进行的系统级了解很少甚至没有 可能会产生哪些漏洞。应激适应癌症细胞器的系统分析 (SASCO) 弗吉尼亚大学中心将通过细胞器过程的机械建模来应对这一挑战 迭代与疾病相关的细胞培养物和原发性肿瘤的定量实验。工作中 SASCO 中心的假设是，细胞器对致癌应激的特异性适应是通过一些因素发生的。 关键瓶颈，一旦相关信号、代谢和运输途径被识别，这些瓶颈就变得可识别 已正确集成。该中心汇集了 14 名主要和协作研究人员 跟踪癌症生物学、系统生物学、基因工程小鼠癌症模型和临床的记录 实践。三个研究项目和一个共享研究核心将追求共同的研究策略， 它利用机械模型来测试关于细胞器如何适应的竞争性替代假设 来自驱动特定类型癌症的近端癌基因的压力。项目已组织 细胞器强调增殖诱导癌基因的下游。项目1将检查 染色体过客复合物及其在中期作为细胞器调节的相分离 感知并修复纺锤体缺陷，以抑制由有丝分裂转录驱动的乳腺癌非整倍性 因素。项目 2 将评估慢性线粒体碎片引起的代谢后果 原发性结直肠癌和继发性肝转移中的突变 KRAS。项目3将调查本地化 信号转导再平衡作为缓解 EGFR 引起的质膜应激的机制 胶质母细胞瘤的扩增。所有研究项目都将依赖高内涵成像和分析核心 获得具有细胞器级分辨率和定量的迭代多通道免疫荧光数据。这 SASCO Outreach Core 扩大了弗吉尼亚大学正在进行的项目，提供夏季研究 来自历史上代表性不足的背景的本科生和教职学者的经历 作为弗吉尼亚州临床医生的介绍性系统生物学建模材料。这 因此，SASCO 中心将在该领域内创建一个亚细胞癌症系统生物学国家总部。 更广泛的癌症系统生物学联盟。