Rachel Hong

Background: Medulloblastomas are the most common malignant brain tumors in children, with the SHH-activated subgroup (SHH-MB) accounting for 30% of medulloblastoma diagnoses.¹ Current treatments rely on varying combinations of radiation therapy, chemotherapy, and stem cell rescue.¹ However, damage during surgical resection occurs in 5-10% of cases, and current chemotherapy options induce long-term neuropsychological and neurocognitive sequelae.¹ Understanding SHH-MB heterogeneities presents opportunities to deploy molecularly-targeted precision therapies.² In that regard, a germline loss-of-function mutation in GPR161, a ciliary G protein-coupled receptor, has been identified in rare cases of infant SHH-MB.^1,2

Objective: In this narrative review, we explore the molecular structures and mechanisms by which GPR161 regulates SHH signaling and how its dysfunction contributes to SHH-MB formation.

Search Methods: An online search in the PubMed database was conducted in the 2018 to 2025 window, using the following keywords: “GPR161,” “Sonic Hedgehog,” and “medulloblastoma.”

Results: In GPR161 conditional knockout mice, tumor formation with high expression of SHH-specific signaling transcripts, granule cell progenitor markers, and histologic markers used in SHH-MB diagnosis was observed.³ Structural modeling of GPR161 revealed similarities to Class A GPCRs, which have an outward-facing transmembrane helix that serves as a Gαs binding interface.⁴ This interaction suppresses SHH signaling: Stimulation of Gαs by GPR161 induces cAMP production, which activates PKA, a kinase that phosphorylates GLI3, a transcription factor, and converts it into a transcriptional repressor.⁵ Silencing GPR161 compromises localization of golgin A5 to the Golgi complex, which results in perturbed Golgi structure.⁶ Whole exome sequencing of a subset of SHH-MB patients revealed germline mutations in GPR161 associated with loss of heterozygosity events (cnLOH) on Chromosome 1q (C1q), establishing this as a signature of SHH-MB predisposition.⁷ Overexpression of melanoma antigen gene (MAGE) proteins was observed in medulloblastoma tumor cell lines.⁸ Transfection with MAGE-A and GAGE specific siRNA oligonucleotides arrested tumor cells in S phase with concomitant induction of caspase-3 expression.⁸ Transplantation of fluorescently-labeled medulloblastoma cell lines, or patient-derived cells, into blastula-stage zebrafish resulted in growth of tumors that homed to the hindbrain within 24 hours.⁹ Extended culturing of such cells in a neural stem cell-like medium enhanced both tumor aggression and the homing phenotype.⁹

Conclusion: The mechanisms by which GPR161 directs normal cerebellar development and prevents SHH-MB formation suggest a role in regulating Golgi structure and protein trafficking, in addition to its role in the cAMP-PKA axis. Moreover, the involvement of cholesterol in GPR161 activation and discovery of melanoma markers in tumor cell lines identify new avenues to investigate in developing next-generation treatments. MAGE and GAGE genes might be attractive targets for chemotherapeutic agents because they are not expressed in normal adult tissues, yet their silencing induces tumor cell sensitivity to chemotherapies and cytotoxicity. The zebrafish model can be leveraged for rapid drug testing, as this model supports efficient tumor growth with precise neurotropism. Clinically, refining our knowledge of GPR161 as part of a heritable predisposition syndrome promises a more rapid diagnosis that, in turn, can inform treatment management by increasing patient surveillance, incorporating genetic counseling, and monitoring at-risk families. In conclusion, GPR161 mutations should be further explored as a driver of SHH-MB, given the role such mutations play in supporting the development of medulloblastoma.

Work Cited:

1. Jackson K, Packer RJ. Recent Advances in Pediatric Medulloblastoma. Curr Neurol Neurosci Rep. 2023;23(12):841-848. doi:10.1007/s11910-023-01316-9
2. Garcia-Lopez J, Kumar R, Smith KS, Northcott PA. Deconstructing Sonic Hedgehog Medulloblastoma: Molecular Subtypes, Drivers, and Beyond. Trends Genet. 2021;37(3):235-250. doi:10.1016/j.tig.2020.11.001
3. Shimada IS, Hwang SH, Somatilaka BN, et al. Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis. Cell Rep. 2018;22(5):1169-1184. doi:10.1016/j.celrep.2018.01.018
4. Hoppe N, Harrison S, Hwang SH, et al. GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway. Nat Struct Mol Biol. 2024;31(4):667-677. doi:10.1038/s41594-024-01223-8
5. Shimada IS, Kato Y. Ciliary signaling in stem cells in health and disease: Hedgehog pathway and beyond. Semin Cell Dev Biol. 2022;129:115-125. doi:10.1016/j.semcdb.2022.04.011
6. Popa S, Villeneuve J, Stewart S, Perez Garcia E, Petrunkina Harrison A, Moreau K. Genome-wide CRISPR screening identifies new regulators of glycoprotein secretion. Wellcome Open Res. 2019;4:119. Published 2019 Aug 9. doi:10.12688/wellcomeopenres.15232.2
7. Begemann M, Waszak SM, Robinson GW, et al. Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma. J Clin Oncol. 2020;38(1):43-50. doi:10.1200/JCO.19.00577
8. Kasuga C, Nakahara Y, Ueda S, et al. Expression of MAGE and GAGE genes in medulloblastoma and modulation of resistance to chemotherapy. Laboratory investigation. J Neurosurg Pediatr. 2008;1(4):305-313. doi:10.3171/PED/2008/1/4/305
9. van Bree N, Oppelt AS, Lindström S, et al. Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing. Neuro Oncol. 2025;27(3):779-794. doi:10.1093/neuonc/noae210