Targeting the tumor matrix as anti-invasive and sensitizing strategy for glioma

描述（申请人提供）：恶性胶质瘤是脑癌中最常见和最致命的一种，具有高度侵袭性和耐放化疗。我们的目标是了解和瞄准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，我们发现并表征了一种新的细胞外基质（ECM）蛋白，称为纤维蛋白-3，它在正常大脑中缺失，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，我们假设纤维蛋白-3在ECM中作为一种扩散因子，通过激活抗凋亡Notch信号和NF-kappaB通路、增加促侵袭基因的表达和控制细胞外基质的降解等机制促进侵袭和细胞存活。因此，抑制纤维蛋白-3可能会减少肿瘤侵袭，使胶质瘤对化疗更敏感。为了验证这些假设，在Specific Aim 1中，我们建议研究纤维蛋白-3促进肿瘤细胞迁移和存活的机制。我们将分析fibuin -3激活Notch通路的机制，以及Notch信号通路介导fibuin -3对细胞侵袭和存活的影响。在具体目标2中，我们建议分析纤维蛋白-3可能促进ECM降解的机制。我们将分析纤维蛋白-3是否通过激活促侵入性NF-kappaB通路和抑制金属蛋白酶抑制剂TIMP3来增加金属蛋白酶活性和ECM降解。最后，在Specific Aim 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。我们将测试一个新的系统来诱导肿瘤中纤维蛋白-3的下调，并分析这种下调对肿瘤生长、侵袭、动物存活以及胶质瘤对标准抗肿瘤药物的敏感性的影响。这些研究的成功完成将确定纤维蛋白-3在脑肿瘤中的作用，并将为支持脑肿瘤进展的机制提供新的见解。这些结果可能转化为新的策略，以破坏肿瘤侵袭和实现更有效的治疗。

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. PUBLIC HEALTH RELEVANCE: Malignant brain tumors, known as gliomas, are one of the types of cancer with worst prognosis. This situation has not improved even after decades of research because these tumors resist conventional chemotherapy and escape novel therapies, thanks, in large part, to their ability to infiltrate in the brain. We propose to characterize and target a novel protein that is secreted by glioma cells but is absent in normal brain. This protein promotes brain tumor invasion and tumor survival, which are the two key processes that reduce the efficacy of current treatments. Therefore, our proposed research is highly relevant because it may lead to effective disruption of tumor progression and increased sensitivity of the tumor to conventional chemotherapeutics. We believe that these studies will have relevance for the development of more effective strategies and therapeutic reagents against malignant brain tumors.