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An ABC Transporter Drives Medulloblastoma Pathogenesis by Regulating Sonic Hedgehog Signaling

Abstract : 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.
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https://hal-u-picardie.archives-ouvertes.fr/hal-03720250
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Soumis le : lundi 11 juillet 2022 - 18:16:38
Dernière modification le : lundi 11 juillet 2022 - 20:01:11

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Juwina Wijaya, Baohan T. Vo, Jingjing Liu, Beisi Xu, Gang Wu, et al.. An ABC Transporter Drives Medulloblastoma Pathogenesis by Regulating Sonic Hedgehog Signaling. CANCER RESEARCH, 2020, 80 (7), pp.1524--1537. ⟨10.1158/0008-5472.CAN-19-2054⟩. ⟨hal-03720250⟩

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