Regulation of Medulloblastoma Metastasis by Emp1

 描述（由申请人提供）：髓母细胞瘤（MB）是儿童中最常见的恶性脑肿瘤。即使采用手术、放疗和化疗的强化方案，25-30%的MB患者仍然死于他们的疾病。虽然绝大多数MB研究都集中在原发性肿瘤上，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。LM最常见于MYC驱动的MB患者，不适合手术切除，并且与极差的患者结局相关。因此，迫切需要了解驱动转移的分子机制，以便开发更有效的治疗方法。使用MYC驱动MB的小鼠模型，其中肿瘤细胞表现出LM，我们最近发现，当注射到脑脊液中时，转移性肿瘤细胞比原发性肿瘤细胞更有可能再生转移性病变。为了确定介导这种转移潜力差异的途径，我们比较了来自我们的动物模型以及MB患者的原发性与转移性肿瘤细胞中的基因表达，并发现tetraspan膜蛋白上皮膜蛋白1（Emp 1）在小鼠和人转移瘤中均显著升高。Emp 1与白血病、淋巴瘤和肺癌的细胞运动、粘附和增殖有关，但从未在MB的背景下进行过研究。在初步研究中，我们发现大部分转移性细胞表达Emp 1，并且在原代MB细胞中Emp 1的过表达增加了它们的体内转移行为。这些数据使我们假设Emp 1可能是转移的标志物和驱动因素。我们将通过确定1）Emp 1是否标记具有增加的转移潜能的细胞和2）Emp 1是否是转移性播散所必需的来测试这一点。这些研究将为MB转移机制提供重要见解，并产生治疗转移性疾病的新方法。

 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.