EGFR signaling network adaptations to overcome RAS-induced membrane stress in glioblastoma

EGFR信号网络适应克服胶质母细胞瘤中RAS诱导的膜应激

基本信息

批准号：
10525284
负责人：
Matthew J Lazzara
金额：
$ 37.64万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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/10525284
关键词：
Accounting Animals Automobile Driving Avidity Binding Biochemical Biological Assay Bioluminescence Cell Death Cell membrane Cells Cessation of life Chemoresistance Chronic Complement Complex Computer Models DNA Damage Data Data Set Disease EGF gene Endocytosis Engineering Epidermal Growth Factor Receptor Equilibrium Exons Glean Glioblastoma Goals Grain Hybrids Hypoxia Image Impairment In Vitro Intervention Investigation Lead Least-Squares Analysis Ligation Location Malignant Neoplasms Malignant neoplasm of brain Maps Measurement Measures Mediating Membrane Modeling Monitor Mutate Mutation NF1 mutation Oncogenes Oncogenic Organelles PIK3CA gene PTEN gene PTPN11 gene Pathway interactions Patients Phenotype Phosphorylation Proteins Proto-Oncogene Proteins c-akt Proto-Oncogenes Receptor Protein-Tyrosine Kinases Regulation Reporter Research Personnel Role Route Signal Transduction Signaling Protein Stress System Systems Analysis Systems Biology Testing Transplantation Tyrosine Phosphorylation Vacuole Work base combinatorial data-driven model epidermal growth factor receptor VIII experimental study immunocytochemistry improved in vivo inhibitor intermolecular interaction interoperability novel strategies predictive modeling protein protein interaction receptor-mediated signaling refractory cancer src Homology Region 2 Domain tool

项目摘要

SUMMARY The most common genetic alteration in glioblastoma (GBM) is amplification of the receptor tyrosine kinase EGFR. In GBM, some amplified EGFR further mutates to yield exon-deleted EGFRvIII, which is constitutively active and endocytosis impaired, thereby signaling to effector pathways that favor survival over proliferation. It is not clear why EGFRvIII is specifically selected for in this disease, but GBM cells poorly tolerate unbridled signaling from the EGFR effector RAS. Chronic RAS signaling places an oncogene-induced stress on cell membranes that gives rise to excessive micropinocytosis and vacuolization, concluding with an alternative form of cell death called methuosis. The objective of this work is to reconcile EGFR amplification and EGFR/RAS-induced membrane stress through EGFRvIII and the signaling intermediates they share. Preliminary evidence suggests that EGFRvIII may achieve stress-relieving signaling adaptations by rewiring the network of protein-protein interactions at different subcellular locations within GBM cells. Our hypothesis is that EGFRvIII is a GBM-specific adaptive mechanism for overcoming methuosis. We will build a computational model of EGFR/EGFRvIII signaling that tests this hypothesis by accounting for the network of protein interactions and signaling relevant for the methuosis phenotype. The specific aims are to 1) define the key intermolecular interactions in the EGFR signaling network and mechanistically predict the consequences of network adaptations to EGFRvIII expression; 2) map differential EGFR signaling network activation among glioblastoma cells to the methuosis phenotype through a hybrid mechanistic and data-driven computational model; and 3) test model predictions about signaling control of methuosis in vitro and in vivo using new tools to monitor RAS-ERK and AKT activities concurrently and noninvasively. This project brings together a team of investigators with complementary expertise in mechanistic and data-driven computational models of receptor- mediated signaling, protein-protein interactions, in vivo transplantations of GBM, and treatment of GBM patients using investigational approaches. By quantitatively testing the hypothesis about EGFRvIII as a key regulator of oncogene-induced plasma membrane stress in glioblastoma, our collaborative project holds promise for identifying conceptually new approaches for driving alternative cell-death phenotypes in a highly chemotherapy-resistant cancer for which durable therapies are desperately needed.

概括胶质母细胞瘤（GBM）中最常见的遗传改变是受体酪氨酸激酶的扩增 egfr。在GBM中，一些扩增的EGFR进一步突变以产生外显子删除的EGFRVIII，这是组成型的活性和内吞作用受损，从而向有利于生存的效应途径发出信号。它尚不清楚为什么在该疾病中专门选择EGFRVIII，但是GBM细胞耐受性不佳来自EGFR效应子RA的信号传导。慢性RAS信号传导将致癌基因引起的应力放在细胞上产生过多的微型细胞增多症和液泡的膜，以替代性结论细胞死亡的形式称为甲基病。这项工作的目的是调和EGFR扩增和 EGFR/RAS通过EGFRVIII诱导的膜应力和它们共享的信号传导。初步证据表明，EGFRVIII可以通过重新布线来实现压力偏移的信号传导适应 GBM细胞内不同亚细胞位置的蛋白质蛋白质相互作用网络。我们的假设是 EGFRVIII是一种克服甲基疾病的GBM特异性适应性机制。我们将建立一个计算 EGFR/EGFRVIII信号传导的模型，该信号通过考虑蛋白质网络来检验该假设相互作用和信号与甲基症表型相关。具体目的是1）定义钥匙 EGFR信号网络中的分子间相互作用，并机械地预测网络适应EGFRVIII表达； 2）映射差异EGFR信号网络激活通过混合机械和数据驱动的计算模型; 3）测试模型的预测有关在体外和体内使用新工具来控制甲基症的信号传导控制同时和无创监视RAS-ERK和AKT活动。该项目汇集了一个团队具有互补专业知识的研究人员在受体的机理和数据驱动计算模型方面介导的信号传导，蛋白质 - 蛋白质相互作用，GBM的体内移植以及GBM的治疗使用研究方法的患者。通过定量测试有关EGFRVIII作为钥匙的假设胶质母细胞瘤中癌基因诱导的质膜胁迫的调节剂，我们的协作项目识别概念上的新方法的希望，用于在高度迫切需要耐用疗法的耐化学疗法癌。