Targeting the Tumor Matrix as Anti-Invasive and Sensitizing Strategy for Glioma

描述(申请人提供)：恶性胶质瘤是最常见和最致命的脑癌类型，具有高度侵袭性，对放射和化疗耐药。我们的目标是了解和靶向驱动肿瘤侵袭和促进胶质瘤细胞存活的机制。在最近的工作中，我们鉴定了一种新的细胞外基质(ECM)蛋白，名为fiBulin-3，它在正常脑中缺失，但在胶质瘤中丰富，并促进肿瘤的生长和侵袭。根据我们的初步结果，我们假设fibuin-3在ECM中作为一个扩散因子，通过激活抗凋亡的Notch信号和NF-kappaB途径，增加侵袭前基因的表达，以及控制细胞外基质的降解，促进侵袭和细胞存活。因此，抑制fiblin-3可能会减少肿瘤的侵袭，并使胶质瘤对化疗更敏感。为了验证这些假说，在特定的目标1中，我们建议研究纤毛蛋白-3促进肿瘤细胞迁移和存活的机制。我们将分析纤维蛋白-3激活Notch通路的机制，以及Notch信号在介导纤维蛋白-3对细胞侵袭和存活影响方面的需求。在具体目标2中，我们建议分析纤毛蛋白-3促进细胞外基质降解的机制。我们将分析fiblin-3是否通过激活前侵袭的NF-kappaB途径和抑制金属蛋白酶抑制剂TIMP3来增加金属蛋白酶的活性和ECM的降解。最后，在特定的目标3中，我们建议评估抑制纤维蛋白-3对肿瘤进展和化疗反应的影响。我们将测试一种新的系统来诱导肿瘤中纤毛蛋白-3的下调，并将分析这种下调对肿瘤生长、侵袭、动物生存和对一种标准护理抗肿瘤药物的增敏的影响。这些研究的成功完成将确定纤毛蛋白-3在脑瘤中的作用，并将为支持脑瘤进展的机制提供新的见解。这些结果可能转化为干扰肿瘤侵袭和实现更有效治疗的新策略。

DESCRIPTION (provided by applicant): Malignant gliomas are the most common and deadly type of brain cancer, highly invasive and resistant to radiation and chemotherapy. Our goal is to understand and target the mechanisms that drive tumor invasion and promote survival in glioma cells. In recent work we identified and characterized a novel extracellular matrix (ECM) protein named fibulin-3, which is absent in normal brain but is abundant in gliomas and promotes tumor growth and invasion. From our preliminary results, we hypothesize that fibulin-3 acts as a diffusible factor in the ECM, promoting invasion and cell survival by mechanisms that may include activation of anti-apoptotic Notch signaling and the NF-kappaB pathway, increased expression of pro-invasive genes, and controlled degradation of the extracellular matrix. Accordingly, inhibition of fibulin-3 may reduce tumor invasion and make gliomas more sensitive to chemotherapeutics. To test these hypotheses, in Specific Aim 1 we propose to investigate the mechanisms by which fibulin-3 promotes tumor cell migration and survival. We will analyze the mechanisms of activation of the Notch pathway by fibulin-3, and the requirement of Notch signaling to mediate the effects of fibulin-3 on cell invasion and survival. In Specific Aim 2 we propose to analyze the mechanisms by which fibulin-3 may promote ECM degradation. We will analyze if fibulin-3 increases metalloprotease activity and degradation of the ECM by activating the pro-invasive NF-kappaB pathway and inhibiting the metalloprotease inhibitor TIMP3. Finally, in Specific Aim 3 we propose to evaluate the impact of suppressing fibulin-3 on tumor progression and response to chemotherapy. We will assay a novel system to induce the downregulation of fibulin-3 in the tumor and will analyze the effect this downregulation on tumor growth, invasion, animal survival, and sensitization of gliomas to a standard-of-care anti-neoplastic drug. Successful completion of these studies will establish the role of fibulin-3 in brain tumors and will provide new insights into the mechanisms that support brain tumor progression. These results may translate into novel strategies to disrupt tumor invasion and achieve more effective therapies.