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.

项目摘要/摘要 致癌基因激活受到执行专业功能的正常亚细胞隔室的调节 与Hallmark癌症表型有关。这些细胞器必须适应致癌应激，以使肿瘤 启动和进步，但是对这种适应的发生方式几乎没有系统级别的理解 可能会创建哪些漏洞。压力适应癌症细胞器（SASCO）的系统分析 弗吉尼亚大学的中心将通过机械模型来应对这一挑战 在与疾病相关的细胞培养和原发性肿瘤中进行定量实验进行迭代。工作 SASCO中心假设是通过一些细胞器特异性适应过度应激。 临界瓶颈，一旦相关信号传导，代谢和传输途径就可以识别 已经正确整合了。该中心汇集了14名调查员 癌症生物学，系统生物学，基因工程癌症模型和临床的记录 实践。三个研究项目和一个共享的研究核心将采取共同的研究策略， 哪些利用机械模型来测试有关细胞器如何适应的竞争替代假设 促进特定类型癌症的近端癌基因的应力。这些项目是组织的 从结构上讲，随着细胞器的压力在下游诱导癌基因的下游。项目1将检查 染色体乘客复合物及其在中期期间的调节相分离为细胞器 感觉和维修纺锤体缺陷以抑制有丝分裂转录驱动的乳腺癌非整倍性 因素。项目2将评估由慢性线粒体片段化的代谢后果 原代结直肠癌和次级肝转移中的突变kras。项目3将调查本地化 信号转移重新平衡作为减轻EGFR引起的血浆膜应激的机制 胶质母细胞瘤的扩增。所有研究项目都将依靠高容量的成像和分析核心 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放大了弗吉尼亚大学正在进行的计划，以提供夏季研究 从历史上代表性不足的背景的本科生和教师学者的经验 作为弗吉尼亚州临床医生的临床医生的入门系统生物学建模材料。这 因此，SASCO中心将创建一个国家的国家总部 更广泛的癌症系统生物联盟。