PTPS-08HEMATOGENOUS DISSEMINATION OF MEDULLOBLASTOMA METASTASES TO THE LEPTOMENINGES

Abstract

Metastatic medulloblastoma is a high-risk disease, because the majority of children dying of medulloblastoma expire from metastases rather than recurrence of the primary tumor. Current dogma dictates that medulloblastoma cells are shed from the primary tumor into the CSF, float through the spinal fluid and establish metastatic colonies on the leptomeningeal surface and spinal cord. Empirical evidence for this mechanism is lacking in the literature. Whole genome sequencing on matched trios of human primary tumor, metastases, and peripheral blood showed somatic mutations from the medulloblastoma at low clonal frequency in the blood samples — consistent with circulating tumor cells. In addition, we identified circulating tumor cells (CTC) in the blood of transgenic mice bearing metastatic medulloblastoma, and in mice intra-cranially implanted with patient derived MB. Surprisingly, when we implanted human or mouse medulloblastoma cells in the flank of immunocompromised mice, the MB cells colonized the leptomeningeal space causing death. As these MB xenografts are not in continuity with the CSF, they must have arisen through hematogenous dissemination. Importantly, flow cytometry shows that MB CTCs express CD34, the cell-surface marker used clinically in children to collect peripheral blood stem cells; suggesting that autologous bone marrow transplants from children with medulloblastoma are likely contaminated with CTCs. Finally we established a parabiosis model where two immunocompromised, sibling mice are surgically joined, and a common blood circulation is established. After parabiosis, one mouse is intra-cranially implanted with MB, and the mice are subsequently separated when the xenografted twin becomes symptomatic. The surviving twin goes on to die from leptomeningeal metastases. Our data challenge the existing paradigm of CSF mediated dissemination of medulloblastoma by demonstrating the capacity of medulloblastoma to spread through the blood system. Identification of a systemic route for MB metastases offers new avenues for the diagnosis and therapy of metastatic medulloblastoma.