Cadherin Regulation of Glioma Invasion: A Biophysical Perspective

项目总结 多形性胶质母细胞瘤(GBM)是一种致命的疾病，没有有效的治疗方法，它与 在所有人类癌症中，5年生存率最差。目前对GBM的治疗很大程度上无效，因为 基底膜肿瘤复发的高倾向，据信部分原因是持续的 特殊的、干细胞样的GBM细胞群称为肿瘤启动细胞(TICs)。此外，转录 研究表明，基底膜复发也与原神经向间充质转化有关。 (PMT)，激活类似的分子程序，使上皮细胞向间充质细胞转化，并赋予促进 基底膜抽搐的侵袭性间质特征，加剧了复发的基底膜。这些后PMT TICS展示 一种高度侵袭性的表型，很容易通过脑实质渗透和扩散，使其非常 通过常规治疗难以消除。对调控机制的重点研究 增强GBM-TIC的运动性是开发有效的GBM治疗的一种有前途的方法。在.期间 PMT、钙粘蛋白发生转换，上调细胞间黏附蛋白Cad-11的表达， 这导致随后细胞迁移能力和定向持久性的增加。当前 研究表明，钙粘素-11可能通过两种机制促进侵袭：1)通过增加 侵袭前蛋白p120连环蛋白(P120)和rac1 GTP酶的表达和活性，以及2)通过 相邻细胞之间产生的细胞间张力，调节肌动蛋白的组织，促进细胞 方向性坚持。值得注意的是，最近的数据确定钙粘附素-11的表达显著 在基底膜肿瘤中表达增加。这项建议试图阐明钙粘蛋白-11在基底膜中的潜在作用。 通过研究钙粘蛋白-11在神经性和间叶性基底膜痉挛中的作用来研究侵袭性。要做到这一点，我们将测试 以下假设：1)钙粘附素-11通过促进基底膜肿瘤的发生和复发 GBM TIC侵袭通过p120和rac1的调节以及细胞-细胞间张力的增加而实现；2) 通过靶向和干扰钙粘蛋白-11信号转导和细胞外信号通路，可以减轻基底膜肿瘤的发生和复发。 生物物理功能。拟议中的研究将是第一次澄清分子和功能的影响。 钙粘蛋白-11在GBM-TIC侵袭中的作用他们还将首先测试钙粘素-11靶向作为一种 GBM的潜在治疗方法。

PROJECT SUMMARY Glioblastoma multiforme (GBM) is a deadly disease with no effective therapy and is associated with one of the worst 5-year survival rates of all human cancers. Current treatments of GBM are largely ineffective due to the high propensity of GBM tumor recurrence, which is believed to be driven in part by the persistence of a specialized, stem-like population of GBM cells called tumor-initiating cells (TICs). Furthermore, transcriptional profiling has indicated that GBM recurrence is also associated with a proneural to mesenchymal transition (PMT), activating similar molecular programs to epithelial to mesenchymal transition and conferring pro- invasive mesenchymal features to GBM TICs, which exacerbate recurrent GBM. These post PMT TICs exhibit a highly invasive phenotype and readily infiltrate and spread through the brain parenchyma making it extremely difficult to eliminate via conventional treatments. Focused investigations of the mechanisms regulating enhanced GBM TIC motility represent a promising approach to developing effective GBM therapy. During PMT, cadherin switching occurs, upregulating the expression of the cell-cell adhesion protein cadherin-11, which leads to subsequent increases in cell migratory capacity and directional persistence. Current investigations indicate that cadherin-11 may promote invasion by two mechanisms: 1) by increasing the expression and activity of pro-invasion proteins p120 catenin (p120) and Rac1 GTPase, and 2) by transmitting intercellular tension generated between neighboring cells, which regulates actin organization and promotes cell directional persistence. Notably, recent data determined that cadherin-11 expression was dramatically increased in GBM tumors. This proposal seeks to elucidate the underlying contributions of cadherin-11 in GBM invasion by studying the role of cadherin-11 in proneural and mesenchymal GBM TICs. To do this, we will test the following hypotheses: 1) Cadherin-11 is responsible for GBM tumorigenesis and recurrence by promoting GBM TIC invasion through the modulation of p120 and Rac1 and through the increase in cell-cell tension; 2) GBM tumorigenesis and recurrence can be mitigated by targeting and disruption cadherin-11 signaling and biophysical function. The proposed studies will be the first to clarify the molecular and functional effect of cadherin-11 in GBM TIC invasion. They will also be the first to test the efficacy of cadherin-11 targeting as a potential therapy for GBM.