The Hippo Pathway in Human Gliomas

人类神经胶质瘤中的 Hippo 通路

• 批准号: 10014747
• 负责人: Jayne Stommel
• 金额: $ 6.92万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10014747
• 关键词: Astrocytes; Binding; Cancerous; Cell Density; Cell Proliferation; Cells; Characteristics; Clinic; Data; Diagnosis; Drug resistance; Epidermal Growth Factor Receptor; Glioblastoma; Glioma; Human; In Vitro; Malignant neoplasm of brain; Mutation; Neuroglia; Pathway interactions; Patients; Platelet-Derived Growth Factor alpha Receptor; Play; Population; Property; Receptor Protein-Tyrosine Kinases; Regimen; Resistance; Role; Stem cells; Survival Rate; Therapeutic; Tyrosine Kinase Inhibitor; Work; cancer stem cell; density; gain of function; in vivo; loss of function; new therapeutic target; overexpression; small hairpin RNA; therapeutic target; therapy resistant; tumor progression; tumorigenesis; tumorigenic

Glioblastoma Multiforme (GBM) is an extremely aggressive brain cancer characterized by rapid progression, high resistance to current therapeutic regimens, and survival rates of only 25% two-years post diagnosis. These characteristics of GBM are attributed to glioblastoma stem cells (GSCs), a highly tumorigenic subpopulation of cancer stem cells that have been identified as the true therapeutic targets for the treatment of GBM. Along these lines, previous studies have attempted to exploit the prevalent amplification and/or mutation of receptor tyrosine kinases (RTKs) within GSCs by treating these cells with tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor alpha (PDGFRA). Although these studies have demonstrated that TKIs are highly effective at reducing cell proliferation in sparse cell populations in vitro, their efficacy in the clinic has been limited. The mechanism underlying this acquired resistance to TKIs in vivo remains to be elucidated. We have data that demonstrate that high cell density in vitro can recapitulate the resistance to TKIs observed in vivo. In recent years, studies have suggested that dysregulation of the Hippo pathway may underlie the progression of cancer, poor overall patient survival and treatment resistance. Since high grade gliomas are positively correlated with expression of TAZ and therapeutic resistant stem cells give rise to GBM, we hypothesize that dysregulation of the Hippo pathway in cancer stem cells may play a significant role in the propagation and sustainment of GBM. Loss-of-function studies using shRNAs against TAZ in GSCs were used to delineate the role of TAZ in high density-dependent drug resistance and tumorigenesis in GBM. Gain-of-function studies using overexpression of TAZ in immortalized normal human astrocytes (NHAs) were used to determine if overexpression of TAZ confers dysregulation of the Hippo pathway that may induce tumorigenic characteristics to nontumorigenic neuroglial cells. Our studies suggest that TAZ is functionally associated with density-dependent resistance to TKIs and multiple tumorigenic characteristics of glioblastoma stem cells. Furthermore, the tumorigenic properties acquired by immortalized NHAs in the presence of TAZ, suggest that dysregulation of the Hippo pathway via overexpression of TAZ may drive transformation of normal neuroglial cells into cancerous cells. An increased understanding of the molecular interactions underlying the functional role of TAZ in density-dependent drug resistance and tumorigenesis will help identify novel therapeutic targets for the treatment of GBM. The work on this project concluded in April 2019.

胶质母细胞瘤多形（GBM）是一种极为侵略性的脑癌，其特征是快速进展，对当前治疗方案的高耐药性和诊断后两年的生存率仅为25％。 GBM的这些特征归因于胶质母细胞瘤干细胞（GSC），这是对癌症干细胞的高度肿瘤亚群的构造，已被确定为治疗GBM的真正治疗靶标。沿着这些线路，先前的研究试图通过用酪氨酸激酶抑制剂（TKI）处理这些细胞来利用GSC中受体酪氨酸激酶（RTK）的普遍扩增和/或突变，以针对表皮生长因子受体（EGFR）或血小板生长因子受体受体受体α（PDGFRA）（PDGFRA）。尽管这些研究表明，TKI在体外稀疏细胞群体的细胞增殖方面非常有效，但它们在临床中的疗效受到限制。这种获得的对TKIS在体内的抗性的机制仍有待阐明。我们有数据表明，体外高细胞密度可以概括体内观察到的TKI的抗性。近年来，研究表明，河马途径的失调可能是癌症进展，总体患者生存率和治疗耐药性不佳的基础。由于高级神经胶质瘤与TAZ的表达呈正相关，并且治疗性抗性干细胞会导致GBM，因此我们假设癌症干细胞中河马途径的失调可能在GBM的传播和维持中起重要作用。使用GSC中使用SHRNA对TAZ的SHRNA的功能丧失研究被用来描述TAZ在GBM中高密度依赖性耐药性和肿瘤发生中的作用。使用TAZ过度表达在永生的正常人星形细胞（NHAS）中进行的功能奖励研究用于确定TAZ的过表达是否会使河马途径的失调失调，这可能会诱导非肿瘤性神经元细胞。我们的研究表明，TAZ在功能上与密度依赖性对TKI的抗性和胶质母细胞瘤干细胞的多个致瘤特性有关。此外，在TAZ存在下，由永生化的NHA获得的致瘤特性表明，通过TAZ过表达对河马途径的失调可能会驱动正常神经细胞转化为癌细胞。对TAZ在密度依赖性耐药性和肿瘤发生中功能作用的基础的分子相互作用的增强理解将有助于确定用于治疗GBM的新型治疗靶标。该项目的工作于2019年4月结束。