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Article Dans Une Revue Cancer Research Année : 2020

An ABC Transporter Drives Medulloblastoma Pathogenesis by Regulating Sonic Hedgehog Signaling

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Juwina Wijaya
  • Fonction : Auteur
Baohan T. Vo
  • Fonction : Auteur
Beisi Xu
  • Fonction : Auteur
Yao Wang
  • Fonction : Auteur
Junmin Peng
  • Fonction : Auteur
Jin Zhang
  • Fonction : Auteur
Laura J. Janke
  • Fonction : Auteur
Brent A. Orr
  • Fonction : Auteur
Martine F. Roussel
  • Fonction : Auteur
  • PersonId : 1157726
John D. Schuetz
  • Fonction : Auteur

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.

Dates et versions

hal-03720250 , version 1 (11-07-2022)

Identifiants

Citer

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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