ATP‐dependent efflux transporter ABCC4 is a positive regulator of the Sonic Hedgehog signaling pathway

Abstract

The Sonic Hedgehog (Hh) signaling pathway is inappropriately activated in multiple malignancies, including basal cell carcinoma and medulloblastoma (MB). MB is the most common malignant pediatric brain tumor, accounting for 20% of all childhood brain tumors. While frontline therapy of MB, which includes tumor resection, radiation, and targeted chemotherapy yields 70% survival rate amongst average‐risk patients, radiation results in devastating neurocognitive impairments, and targeted therapy can give rise to drug‐resistant tumors. As such, further advances in therapy of MB will require identification of factors that modulate Hh pathway. We discovered that ABCC4 was, along with other Hh pathway genes, specifically over‐expressed in Hh‐driven MB. High ABCC4 expression was associated with significantly worse overall survival in Hh‐driven MB patients. In Hh pathway cellular model systems, ligand‐dependent pathway activation or loss of negative regulators upregulated ABCC4 expression, suggesting ABCC4 has a positive regulatory role and that blocking expression may impair signaling. Ablation of Abcc4 suppressed both normal, ligand‐dependent signaling as well as aberrant, cancer‐like, ligand‐independent signaling. Furthermore, targeted Abcc4 ablation using CRISPR technology in a murine model of Hh‐MB tumor extended survival of Hh tumor‐bearing mice. This study reveals ABCC4 as a critical regulator of the Hh pathway that contributes to MB pathogenesis and present a new molecular target and opportunity to improve therapy against Hh‐driven tumors.Support or Funding InformationThis work was supported by ALSAC and NIH P30CA021765 Cancer Center Support GrantThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.