2. Academic Validation
  3. FOXD1-ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells

FOXD1-ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells

  • Cancer Res. 2016 Dec 15;76(24):7219-7230. doi: 10.1158/0008-5472.CAN-15-2860.
Peng Cheng 1 2,  Jia Wang 1 3,  Indrayani Waghmare 4,  Stefania Sartini 5,  Vito Coviello 5,  Zhuo Zhang 1,  Sung-Hak Kim 1,  Ahmed Mohyeldin 6,  Marat S Pavlyukov 1,  Mutsuko Minata 1,  Claudia L L Valentim 7,  Rishi Raj Chhipa 8,  Krishna P L Bhat 9,  Biplab Dasgupta 8,  Concettina La Motta 5,  Madhuri Kango-Singh 4,  Ichiro Nakano 10 11
Affiliations

Affiliations

  • 1 Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.
  • 2 Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.
  • 3 Department of Neurosurgery, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 4 Department of Biology, University of Dayton, Dayton, Ohio.
  • 5 Department of Pharmacy, University of Pisa, Pisa, Italy.
  • 6 Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
  • 7 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • 8 Department of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
  • 9 Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
  • 10 Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama. inakano@uabmc.edu.
  • 11 Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
PMID: 27569208 DOI: 10.1158/0008-5472.CAN-15-2860
Abstract

Glioma stem-like cells (GSC) with tumor-initiating activity orchestrate the cellular hierarchy in glioblastoma and engender therapeutic resistance. Recent work has divided GSC into two subtypes with a mesenchymal (MES) GSC population as the more malignant subtype. In this study, we identify the FOXD1-ALDH1A3 signaling axis as a determinant of the MES GSC phenotype. The transcription factor FOXD1 is expressed predominantly in patient-derived cultures enriched with MES, but not with the proneural GSC subtype. shRNA-mediated attenuation of FOXD1 in MES GSC ablates their clonogenicity in vitro and in vivo Mechanistically, FOXD1 regulates the transcriptional activity of ALDH1A3, an established functional marker for MES GSC. Indeed, the functional roles of FOXD1 and ALDH1A3 are likely evolutionally conserved, insofar as RNAi-mediated attenuation of their orthologous genes in Drosophila blocks formation of brain tumors engineered in that species. In clinical specimens of high-grade glioma, the levels of expression of both FOXD1 and ALDH1A3 are inversely correlated with patient prognosis. Finally, a novel small-molecule inhibitor of ALDH we developed, termed GA11, displays potent in vivo efficacy when administered systemically in a murine GSC-derived xenograft model of glioblastoma. Collectively, our findings define a FOXD1-ALDH1A3 pathway in controling the clonogenic and tumorigenic potential of MES GSC in glioblastoma tumors. Cancer Res; 76(24); 7219-30. ©2016 AACR.

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