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.
Patients with metastatic medulloblastoma face a grim prognosis, because metastatic lesions cannot be surgically removed and are unresponsive to most therapies. Our studies focus on Emp1, a membrane protein that we have found to be expressed at high levels in metastatic cells from both mouse and human medulloblastoma. Elucidating the role of Emp1 in metastasis will provide insight into the molecular basis of metastasis and yield novel approaches for treating metastatic disease.
|Kahn, Suzana A; Wang, Xin; Nitta, Ryan T et al. (2018) Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma. Nat Commun 9:4121|