Editors' ChoiceMedulloblastoma

The long(er) road from brain to meninges

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Science Translational Medicine  14 Mar 2018:
Vol. 10, Issue 432, eaas8970
DOI: 10.1126/scitranslmed.aas8970

Abstract

Medulloblastoma spreads from the cerebellum to the leptomeninges via blood in addition to cerebrospinal fluid.

Medulloblastoma (a pediatric brain tumor) is a devastating disease for a young population and the families that love them. Even after surgery to remove the cerebellar tumor, spread of this disease to the leptomeninges—the membranes that surround the brain and spinal cord—can result in death. Standard of care dictates prophylactic radiation of the entire brain and spinal cord in all children over three years old, an extreme treatment to prevent disease spread that results in significant long-term side effects. Because medulloblastoma develops directly adjacent to cerebrospinal fluid (CSF) space, the neuro-oncology community assumed tumor cells were shed and floated into CSF, ultimately spreading to the leptomeninges. Clinical and research efforts have therefore focused on the primary tumor and the cerebrospinal fluid as the route of metastasis.

Garzia et al. first noted a potential flaw in this theory after using whole genome sequencing to evaluate patient samples of tumor, metastasis, and peripheral blood. Not only were circulating tumor cells (CTCs) identified in blood, but deep sequencing suggested that subpopulations of CTCs released by tumors clonally adapt to form leptomeningeal metastases. In vivo insertion of fluorescently tagged patient-derived tumors into mouse flanks (where there is no contact with CSF) still showed spread to the leptomeningeal compartment. The authors took this a step further, using a parabiosis model where two sibling mice were surgically grafted to one another to allow for shared circulation. Implantation of a tumor in the cerebellum of one mouse resulted in leptomeningeal metastasis in the attached sibling up to 50% of the time.

Noting that patient leptomeningeal metastases show elevated CCL2, a chemokine involved in neuroinflammatory processes, the authors up-regulated CCL2 and its receptor CCR2 in vivo in mice, reproducibly increasing incidence and size of leptomeningeal metastases. Not surprisingly, CCL2 resides on chromosome 17q, and gain of chromosome 17q is seen in specific medulloblastoma subtypes associated with advanced metastasis.

The majority of cancers metastasize through blood. Thus, it isn’t surprising that medulloblastoma does so as well; proximity of tumor to CSF may have been a red herring for decades. Most critically, however, identification of this hematogenous tumor niche and CCL2 target now offers new research avenues for diagnosis, monitoring, and therapy of this destructive disease.

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