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 Sonic Hedgehog (SHH) subgroup of MB (SHH-MB) is driven by aberrant activation of the 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 GLI family zinc finger 1 (GLI1) in both the developing cerebellum and medulloblastoma. GPC6 promotes cell proliferation, migration, and invasion in SHH-MB cell lines (DAOY and ONS-76). Consistently, GPC6 enhances the SHH pathway activity by upregulating GLI1 expression, supports ciliogenesis essential for signal transduction, and facilitates SHH ligand expression via extracellular vesicles. These findings suggest that GPC6 acts as a key regulator of SHH signaling and represents a potential therapeutic target in SHH-MB.