A synthetic systems biology approach to predict context-specific mechanisms for SHP2 functional activity and resistance to SHP2 inhibition

一种合成系统生物学方法，用于预测 SHP2 功能活性和 SHP2 抑制抗性的特定机制

• 批准号: 10831287
• 负责人: Kevin A Janes
• 金额: $ 16.7万
• 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/10831287
• 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; PTPN11 gene; Pathway interactions; Phase; Phenotype; Pilot Projects; Play; Positioning Attribute; Primary Neoplasm; Process; Proliferating; Records; Recurrence; Research; Research Personnel; Research Project Grants; Resistance; 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.

项目总结/摘要 癌基因的激活是由执行特殊功能的正常亚细胞区室调节的 与标志性癌症表型有关。这些细胞器必须适应致癌应激， 启动和进展，但很少或根本没有系统级的了解如何发生这种适应， 可能会产生哪些漏洞。应激适应癌细胞器的系统分析 中心将通过对细胞器过程的机械建模来解决这一挑战 在疾病相关的细胞培养和原发性肿瘤中进行定量实验。工作 SASCO中心的假设是，细胞器特异性适应致癌应激发生通过一些 关键的瓶颈，一旦相关的信号传导，代谢和运输途径变得可识别 已被妥善整合。该中心汇集了14名研究人员， 在癌症生物学、系统生物学、癌症的基因工程小鼠模型和临床 实践三个研究项目和一个共享的研究核心将追求一个共同的研究战略， 它利用机械模型来测试关于细胞器如何适应 来自驱动特定类型癌症的近端癌基因的压力。项目组织 细胞器压力在增殖诱导癌基因的下游。项目1将审查 染色体乘客复合体及其作为细胞器在中期调控相分离 检测并修复纺锤体缺陷，以抑制由有丝分裂转录驱动的乳腺癌非整倍体 因素项目2将评估慢性线粒体断裂的代谢后果， 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减轻EGFR引起的质膜应激的机制 胶质母细胞瘤中的扩增。所有研究项目都将依赖于高内容成像和分析核心， 获得具有细胞器水平分辨率和定量的迭代多通道免疫荧光数据。的 SASCO外展核心放大正在进行的计划在弗吉尼亚大学提供夏季研究 本科生和教师学者的经验，从历史上代表性不足的背景，以及 作为弗吉尼亚州临床医生的系统生物学建模入门材料。的 因此，SASCO中心将在2015年建立一个亚细胞癌症系统生物学的国家总部。 癌症系统生物学联盟