title: Molecular heterogeneity in a patient-derived glioblastoma xenoline is regulated by different cancer stem cell populations.
abstract: Malignant glioblastoma (GBM) is a highly aggressive brain tumor with a dismal prognosis and limited therapeutic options. Genomic profiling of GBM samples has identified four molecular subtypes (Proneural, Neural, Classical and Mesenchymal), which may arise from different glioblastoma stem-like cell (GSC) populations. We previously showed that adherent cultures of GSCs grown on laminin-coated plates (Ad-GSCs) and spheroid cultures of GSCs (Sp-GSCs) had high expression of stem cell markers (CD133, Sox2 and Nestin), but low expression of differentiation markers (βIII-tubulin and glial fibrillary acid protein). In the present study, we characterized GBM tumors produced by subcutaneous and intracranial injection of Ad-GSCs and Sp-GSCs isolated from a patient-derived xenoline. Although they formed tumors with identical histological features, gene expression analysis revealed that xenografts of Sp-GSCs had a Classical molecular subtype similar to that of bulk tumor cells. In contrast xenografts of Ad-GSCs expressed a Mesenchymal gene signature. Adherent GSC-derived xenografts had high STAT3 and ANGPTL4 expression, and enrichment for stem cell markers, transcriptional networks and pro-angiogenic markers characteristic of the Mesenchymal subtype. Examination of clinical samples from GBM patients showed that STAT3 expression was directly correlated with ANGPTL4 expression, and that increased expression of these genes correlated with poor patient survival and performance. A pharmacological STAT3 inhibitor abrogated STAT3 binding to the ANGPTL4 promoter and exhibited anticancer activity in vivo. Therefore, Ad-GSCs and Sp-GSCs produced histologically identical tumors with different gene expression patterns, and a STAT3/ANGPTL4 pathway is identified in glioblastoma that may serve as a target for therapeutic intervention.
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
authors.forename: Jo Meagan
authors.initials: JM
authors.lastname: Garner
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
authors.forename: Debolina
authors.initials: D
authors.lastname: Ganguly
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
authors.forename: Ziyun
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sims
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
authors.forename: Chuan He
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America; Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, United States of America.
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: Interiano
authors.affiliation: Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America; Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, United States of America.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, United States of America.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002469:Cell Separation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018740:Genetic Heterogeneity; D005909:Glioblastoma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D016513:Mice, SCID; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D040521:Subcutaneous Tissue / Q000473:pathology; D016019:Survival Analysis; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D011725:Pyridines; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C519885:WP1066