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

项目摘要/摘要 癌基因的激活是由执行特殊功能的正常亚细胞室调节的。 与标志性癌症表型有关。这些细胞器必须适应致癌压力才能形成肿瘤。 以启动和进步，但对于这种适应如何发生和发展，几乎没有系统层面的理解 可能会产生哪些漏洞。应激适应肿瘤细胞器(SASCO)的系统分析 弗吉尼亚大学的中心将通过对细胞器过程的机械建模来解决这一挑战 这与疾病相关细胞培养和原发肿瘤的定量实验重复。在工作中 萨斯科中心假说认为，细胞器对致癌应激的特异性适应是通过几个 关键瓶颈，一旦相关的信号、代谢和运输途径 已经被适当地整合了。该中心汇集了14名调查人员，主要和合作 在癌症生物学、系统生物学、癌症基因工程小鼠模型和临床方面的记录 练习一下。三个研究项目和一个共享研究核心将实行共同的研究战略， 它利用机械模型来测试关于细胞器如何适应的相互竞争的替代假设 来自导致特定类型癌症的近端癌基因的压力。这些项目是有组织的 作为细胞器压力的层级，在增殖诱导癌基因的下游。项目1将检查 染色体乘客复合体及其作为细胞器在中期的调控相分离 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体 各种因素。项目2将评估慢性线粒体碎裂引起的代谢后果 突变的KRAS在原发性结直肠癌和继发性肝转移中的作用。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高内容成像和分析核心，以 获得细胞器水平分辨率和量化的迭代多通道免疫荧光数据。这个 SASCO扩展核心扩大了弗吉尼亚大学正在进行的项目，以提供夏季研究 来自历史代表性不足背景的本科生和教职员工学者的经验也是如此 作为弗吉尼亚州联邦临床医生的系统生物学模型入门材料。这个 因此，SASCO中心将在全球范围内建立亚细胞癌症系统生物学的国家总部 更广泛的癌症系统生物学联盟。

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.