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 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.