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Medulloblastoma (MB) is the most common malignant pediatric brain tumor [10]. Although continued advances have been made in our understanding of medulloblastoma, questions remain about its etiology and treatment [3, 4, 7, 9, 13–15, 17, 18]. Medulloblastoma is classified into four demographically, clinically, and molecularly distinct subgroups called WNT, SHH, Group 3 and Group 4 (As reviewed in [19]), and further divided into additional distinct molecular subtypes [3, 14]. While patients with (WNT) pathway driven medulloblastoma have favorable outcomes, recurrence rates are higher in other subtypes such as SHH, which tend to recur locally, and Group 3 and 4, which are associated with distal metastases [16]. The biology of metastatic medulloblastoma is distinct from primary medulloblastoma; representing potentially a different therapeutic disease [6, 8, 13]. Approaches are needed to identify pathways of therapy resistance in both primary and metastatic compartments of medulloblastoma to guide selection of targeted therapies. As an example, the MET proto-oncogene is upregulated in SHH and Group 3 medulloblastoma, and can be targeted by treatment of cells and mouse models with the small molecule inhibitor, Foretinib [4]. We utilized a spontaneous metastatic mouse model of medulloblastoma driven by the Sleeping Beauty mutagenesis transposon system [21] to pinpoint functional drivers and pathways of resistance to Foretinib [4] in both primary and metastatic medulloblastoma. This serves as a novel approach to dissecting patterns of therapy resistance at multiple tumor sites simultaneously which can be readily applied to other cancer systems.

A functional genomics approach to identify pathways of drug resistance in medulloblastoma