title: FOXD1-ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells.
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.
authors: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.|Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.
authors: Peng
authors: P
authors: Cheng
authors: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.|Department of Neurosurgery, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors: Jia
authors: J
authors: Wang
authors: Department of Biology, University of Dayton, Dayton, Ohio.
authors: Indrayani
authors: I
authors: Waghmare
authors: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors: Stefania
authors: S
authors: Sartini
authors: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors: Vito
authors: V
authors: Coviello
authors: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.
authors: Zhuo
authors: Z
authors: Zhang
authors: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.
authors: Sung-Hak
authors: SH
authors: Kim
authors: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors: Ahmed
authors: A
authors: Mohyeldin
authors: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.
authors: Marat S
authors: MS
authors: Pavlyukov
authors: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.
authors: Mutsuko
authors: M
authors: Minata
authors: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors: Claudia L L
authors: CL
authors: Valentim
authors: Department of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Rishi Raj
authors: RR
authors: Chhipa
authors: Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors: Krishna P L
authors: KP
authors: Bhat
authors: Department of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Biplab
authors: B
authors: Dasgupta
authors: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors: Concettina
authors: C
authors: La Motta
authors: Department of Biology, University of Dayton, Dayton, Ohio.
authors: Madhuri
authors: M
authors: Kango-Singh
authors: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama. inakano@uabmc.edu.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
authors: Ichiro
authors: I
authors: Nakano
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D004330:Drosophila; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D014411:Neoplastic Stem Cells / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C500800:FOXD1 protein, human; D051858:Forkhead Transcription Factors; D000445:Aldehyde Oxidoreductases; C018699:aldehyde dehydrogenase (NAD(P)+)