GPC6 facilitates progression of SHH-subgroup medulloblastoma by enhancing Hedgehog secretion and signaling responses

Medulloblastoma (MB) is the most common malignant tumor of the cerebellum in children. The SHH subgroup of MB (SHH-MB) is driven by aberrant activation of the Sonic Hedgehog (SHH) pathway; however, mutations in genes related to this pathway are relatively rare, posing challenges for therapeutic development. Glypican-6 (GPC6), a heparan sulfate proteoglycan, is highly expressed in SHH-MB. In this study, we demonstrate the synchronous expression of GPC6 with GLI1 in both the developing cerebellum and medulloblastoma. GPC6 promoted the cell proliferation, migration, and invasion in SHH-MB cell lines (DAOY and ONS-76). Consistently, GPC6 enhanced SHH pathway activity by upregulating GLI1 expression, supported ciliogenesis that is essential for signal transduction, and facilitated the secretion of SHH ligands via extracellular vesicles. These findings establish GPC6 as a critical regulator of SHH-MB progression and highlight its potential as a therapeutic target.