An ABC Transporter Drives Medulloblastoma Pathogenesis by Regulating Sonic Hedgehog Signaling
Résumé
Mutations in Sonic hedgehog (SHH) signaling promote aberrant proliferation and tumor growth. SHH-medulloblastoma (MB) is among the most frequent brain tumors in children less than 3 years of age. Although key components of the SHH pathway are well-known, we hypothesized that new disease-modifying targets of SHH-MB might be identified from large-scale bioinformatics and systems biology analyses. Using a data-driven systems biology approach, we built a MB-specific interactome. The ATP-binding cassette transporter ABCC4 was identified as a modulator of SHH-MB. Accordingly, increased ABCC4 expression correlated with poor overall survival in patients with SHH-MB. Knockdown of ABCC4 expression markedly blunted the constitutive activation of the SHH pathway secondary to Ptch1 or Sufu insufficiency. In human tumor cell lines, ABCC4 knockdown and inhibition reduced full-length GLI3 levels. In a clinically relevant murine SHH-MB model, targeted ablation of Abcc4 in primary tumors significantly reduced tumor burden and extended the lifespan of tumor-bearing mice. These studies reveal ABCC4 as a potent SHH pathway regulator and a new candidate to target with the potential to improve SHH-MB therapy. SIGNIFICANCE: These findings identify ABCC4 transporter as a new target in SHH-MB, prompting the development of inhibitors or the repurporsing of existing drugs to target ABCC4.
Mots clés
Animal
Animals
Brain Neoplasms
Cell Line
Child
Datasets as Topic
Disease Models
Follow-Up Studies
Gene Expression Regulation
Gene Knockdown Techniques
Hedgehog Proteins
Humans
Kaplan-Meier Estimate
Knockout
Medulloblastoma
Mice
Multidrug Resistance-Associated Proteins
Neoplastic
Nerve Tissue Proteins
NIH 3T3 Cells
Protein Interaction Mapping
Protein Interaction Maps
Signal Transduction
Systems Biology
Tumor
Tumor Burden
Xenograft Model Antitumor Assays
Zinc Finger Protein Gli3