SYST-07 PLASMA MEMBRANE PROFILING REVEALS A TARGETABLE CELL-SURFACE PHENOTYPE OF WNT-MEDULLOBLASTOMA

Abstract WNT-medulloblastoma has an excellent prognosis, with overall survival rate of 90% among children receiving standard-of-care surgical resection, radiotherapy, and chemotherapy. While curative, this treatment is associated major, long-term, debilitating side effects. Therefore, it crucial we develop effective, less toxic therapies for these children. The Gilbertson lab previously shown that WNT-medulloblastomas are devoid a Blood-Brain-Barrier (BBB). This disruption allows large molecules such as monoclonal antibodies (mAbs) to penetrate WNT-medulloblastomas. To discover specific antigens mAb targeting, have first generated bulk single-cell RNA sequencing profiles the wild-type WNT-medulloblastoma-prone mossy-fibre progenitor lineages in lower rhombic lip, well human medulloblastoma patient derived orthotopic xenograft (PDOX) tumours. We next plasma membrane proteome hindbrain germinal zones Plasma Membrane Profiling (PMP) deploys isobaric chemical labelling approach -Tandem Mass Tags (TMT) - multiplexing up sixteen variables per mass spectrometry experiment ex vivo TMT-labelling primary cells. Using approach, mapped cell surface our models. Interrogation developmental tumour data unmasked prenatal brain WNT-medulloblastoma, but not expressed on critical postnatal tissues. Our workflow integrates multi-omic sets uncover targetable landscape cells cross-validated cohort histological samples both mouse translate dataset real benefit, generating high affinity validated cell-surface proteins assessment pre-clinical Through comparative analyses additionally identified non-WNT-specific targets thus aim expand identifying other more agressive CNS tumours metastases.