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AMBRA1 as a novel positive regulator of the SHH pathway in medulloblastoma [RNA-Seq]

ABSTRACT: AMBRA1 (Autophagy and Beclin 1 Regulator 1) is a versatile scaffold protein involved in disparate processes including autophagy, cell cycle regulation, and tumorigenesis. While AMBRA1 is primarily recognized as a tumor suppressor, its dual function as a tumor promoter has garnered increasing attention. However, the role of AMBRA1 remains largely unexplored in many malignancies, particularly in brain tumors. Leveraging multiomic analysis of the largest human medulloblastoma (MB) cohort, we identify significantly elevated AMBRA1 protein levels in the Sonic Hedgehog subgroup (MBSHH) compared to other MB variants. Notably, AMBRA1 protein abundance, independent of its mRNA expression, correlates with poor prognosis, positioning AMBRA1 as a biomarker for MBSHH. Mechanistically, AMBRA1 enhances SHH signaling by stabilizing GLI1, the pathway's final effector, by inhibiting the βTrCP-mediated degradation of GLI1. Additionally, AMBRA1 protein stability is modulated by the REN E3 ubiquitin ligase, a tumor suppressor gene and antagonist of the SHH pathway. Genetic inhibition of AMBRA1 significantly blocks MBSHH growth in murine and patient-derived pre-clinical models, highlighting its therapeutic potential. Moreover, combining AMBRA1 knock-down with FDA-approved SHH inhibitors amplifies tumor suppression. These findings uncover the AMBRA1/βTrCP/REN axis as a key regulatory mechanism in SHH signaling, providing actionable insights into targeted therapies for MBSHH.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288462 | GEO | 2026/03/09

REPOSITORIES: GEO

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Project description:Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHH subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

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AMBRA1 as a novel positive regulator of the SHH pathway in medulloblastoma [RNA-Seq]

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