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) 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，产生外显子缺失的 EGFRvIII，这是组成型的活性和内吞作用受损，从而向有利于生存而不是增殖的效应途径发出信号。它目前尚不清楚为什么特意选择 EGFRvIII 来治疗这种疾病，但 GBM 细胞对肆无忌惮的耐受性很差来自 EGFR 效应器 RAS 的信号传导。慢性 RAS 信号传导对细胞施加致癌基因诱导的应激膜引起过度的微胞饮作用和空泡化，最后得出替代方案细胞死亡的一种形式称为methuosis。这项工作的目的是协调 EGFR 扩增和 EGFR/RAS 通过 EGFRvIII 及其共享的信号中间体诱导膜应激。初步证据表明 EGFRvIII 可能通过重新布线实现缓解压力的信号适应 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 GBM 特异性的克服 methuosis 的适应性机制。我们将建立一个计算 EGFR/EGFRvIII 信号传导模型通过考虑蛋白质网络来检验这一假设与methuosis表型相关的相互作用和信号传导。具体目标是 1) 定义关键 EGFR 信号网络中的分子间相互作用并从机制上预测其后果网络适应 EGFRvIII 表达； 2) 绘制差异EGFR信号网络激活图通过混合机制和数据驱动的计算将胶质母细胞瘤细胞转变为methuosis表型模型; 3）使用新工具在体外和体内测试有关方法的信号控制的模型预测同时、无创地监测 RAS-ERK 和 AKT 活动。这个项目汇集了一个团队在受体机械和数据驱动计算模型方面具有互补专业知识的研究人员介导的信号传导、蛋白质-蛋白质相互作用、GBM 体内移植以及 GBM 治疗使用研究方法的患者。通过定量检验 EGFRvIII 作为关键的假设胶质母细胞瘤中癌基因诱导的质膜应激的调节因子，我们的合作项目举行有望确定概念上新的方法，以高度驱动替代细胞死亡表型迫切需要持久治疗的化疗耐药性癌症。