Sonic hedgehog subgroup medulloblastoma (SHH-MB), an aggressive pediatric brain tumor that originates from granule neuron precursors, faces the challenge of poor treatment owing to its unclear molecular mechanisms. Here, we show that sialic acid-binding immunoglobulin-like receptor 15 (Siglec-15), an immunosuppressive membrane protein, is upregulated and mediates SHH-MB growth through its translocation to the lysosomal membrane. We found that SHH-MB cells use the cation-independent mannose 6-phosphate receptor (CI-MPR) to transport Siglec-15 from the trans-Golgi network (TGN) to lysosomes, where Siglec-15 induces lysosomal Ca2+ release by interacting with mucolipin TRP cation channel 1 (TRPML1), leading to the nuclear translocation of the transcription factor EB (TFEB). Blockade of Siglec-15, TRPML1, or TFEB hinders SHH-MB growth in vitro and in vivo. Importantly, aryl hydrocarbon receptor (AhR), a cytoplasmic transcription factor, upregulates Siglec-15 expression. AhR inhibition by CH-223191 or StemRegenin 1 (SR1) achieved therapeutic efficacy against orthotopic SHH-MB xenografts in mice. These findings reveal an essential role for the AhR-Siglec-15 axis in SHH-MB development, providing a potential strategy for SHH-MB treatment.
Keywords: AhR; Siglec-15; TFEB; TRPML1; lysosome.
© The Author(s) 2025. Published by Oxford University Press on behalf of Higher Education Press.