Regulation of Medulloblastoma Metastasis by Emp1

 描述(申请人提供)：髓母细胞瘤(MB)是儿童最常见的恶性脑肿瘤。即使采用密集的手术、放疗和化疗方案，仍有25%-30%的MB患者死于他们的疾病。虽然绝大多数MB研究都集中在原发肿瘤上，但相对较少研究软脑膜转移(LM)的生物学，即肿瘤细胞通过脑膜扩散到大脑和脊髓。肌萎缩侧索硬化症最常见于肌萎缩侧索硬化症患者，它不适合手术切除，与极差的患者预后有关。因此，迫切需要了解肿瘤转移的分子机制，以便开发更有效的治疗方法。利用MYC驱动的MB小鼠模型，其中肿瘤细胞表现为LM，我们最近发现，当将转移瘤细胞注射到脑脊液中时，转移瘤细胞比原发肿瘤细胞更有可能再生转移灶。为了确定介导这种转移潜能差异的途径，我们比较了我们的动物模型和MB患者的原发和转移肿瘤细胞中的基因表达，发现Tetraspan膜蛋白上皮膜蛋白1(EMP1)在小鼠和人类转移瘤中都显著升高。EMP1与白血病、淋巴瘤和肺癌的细胞运动、黏附和增殖有关，但从未在MB的背景下进行过研究。在初步研究中，我们发现很大比例的转移细胞表达EMP1，并且在原代MB细胞中过表达EMP1会增加其体内的转移行为。这些数据使我们假设EMP1可能作为转移的标志物和驱动因素发挥作用。我们将通过确定1)EMP1是否标记转移潜能增加的细胞以及2)是否需要EMP1进行转移扩散来测试这一点。这些研究将为MB的转移机制提供关键的洞察力，并产生治疗转移疾病的新方法。

 DESCRIPTION (provided by applicant): Medulloblastoma (MB) is the most common malignant brain tumor in children. Even with an intensive regimen of surgery, radiation and chemotherapy, 25-30% of MB patients still die from their disease. While the vast majority of MB studies have focused on primary tumors, relatively few have examined the biology of leptomeningeal metastasis (LM), the spread of tumor cells through the meninges to the brain and spinal cord. LM, most commonly seen in patients with MYC-driven MB, is not amenable to surgical resection and is associated with extremely poor patient outcomes. Thus, there is a critical need to understand the molecular mechanisms driving metastasis so that more effective therapies can be developed. Using a mouse model of MYC-driven MB in which tumor cells exhibit LM, we recently found that metastatic tumor cells are more likely than primary tumor cells to regenerate metastatic lesions when injected into the cerebrospinal fluid. To identify pathways that mediate this difference in metastatic potential, we compared gene expression in primary vs. metastatic tumor cells from our animal model as well as from MB patients, and found that the tetraspan membrane protein Epithelial membrane protein 1 (Emp1) is significantly elevated in both murine and human metastases. Emp1 has been implicated in cell motility, adhesion and proliferation in leukemia, lymphoma and lung cancer, but has never been studied in the context of MB. In preliminary studies we found that a large proportion of metastatic cells express Emp1, and that overexpression of Emp1 in primary MB cells increases their metastatic behavior in vivo. These data have led us to hypothesize that Emp1 may function as a marker and a driver of metastasis. We will test this by determining 1) whether Emp1 marks cells with increased metastatic potential and 2) whether Emp1 is required for metastatic dissemination. These studies will provide critical insight into the mechanisms of metastasis in MB and yield novel approaches for treating metastatic disease.