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

• 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
• 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

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.

总结 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对在GBM中，一些扩增的EGFR进一步突变以产生外显子缺失的EGFRvIII，其是组成性的。 活性和内吞作用受损，从而向有利于存活而不是增殖的效应子途径发出信号。它 目前尚不清楚为什么EGFRvIII是专门选择在这种疾病，但GBM细胞耐受不良肆无忌惮的 从EGFR效应器RAS的信号传导。慢性RAS信号传导对细胞产生癌基因诱导的应激 膜，引起过度的微胞饮和空泡化，最后与替代 细胞死亡的一种形式，称为死亡。这项工作的目的是协调EGFR扩增和 EGFR/RAS通过EGFRvIII和它们共享的信号中间体诱导的膜应激。 初步证据表明，EGFRvIII可能通过重新布线来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特异性的适应机制，用于克服记忆障碍。我们将建立一个计算 EGFR/EGFRvIII信号传导模型，通过解释蛋白质网络来检验这一假设 相互作用和信号转导相关的methuosis表型。具体目标是：1）定义密钥 EGFR信号网络中的分子间相互作用，并在机制上预测 网络适应EGFRvIII表达; 2）映射差异EGFR信号传导网络激活， 通过混合机制和数据驱动的计算， 模型;以及3）使用新工具在体外和体内测试关于方法学的信号控制的模型预测， 监测RAS-ERK和AKT活性同时和非侵入性。这个项目汇集了一个团队， 研究人员在受体的机械和数据驱动的计算模型方面具有互补的专业知识， 介导的信号传导、蛋白质-蛋白质相互作用、GBM的体内移植和GBM的治疗 患者使用研究方法。通过定量检验关于EGFRvIII作为关键因子的假设， 在胶质母细胞瘤中癌基因诱导的质膜应激的调节剂，我们的合作项目持有 在一个高度复杂的环境中， 耐化疗的癌症，迫切需要持久的治疗方法。