Molecular heterogeneity in a patient-derived glioblastoma xenoline is regulated by different cancer stem cell populations

Jo Meagan Garner, David W. Ellison, David Finkelstein, Debolina Ganguly, Ziyun Du, Michelle Sims, Chuan Yang, Rodrigo B. Interiano, Andrew M. Davidoff, Lawrence Pfeffer

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere0125838
JournalPLoS ONE
Volume10
Issue number5
DOIs
StatePublished - May 1 2015

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Neoplastic Stem Cells
Glioblastoma
Stem cells
stem cells
Tumors
neoplasms
Heterografts
gene expression
Population
Stem Cells
Gene expression
therapeutics
Genes
laminin
stems
Cells
Gene Expression
neuroglia
Nestin
tubulin

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Molecular heterogeneity in a patient-derived glioblastoma xenoline is regulated by different cancer stem cell populations. / Garner, Jo Meagan; Ellison, David W.; Finkelstein, David; Ganguly, Debolina; Du, Ziyun; Sims, Michelle; Yang, Chuan; Interiano, Rodrigo B.; Davidoff, Andrew M.; Pfeffer, Lawrence.

In: PLoS ONE, Vol. 10, No. 5, e0125838, 01.05.2015.

Research output: Contribution to journalArticle

Garner, JM, Ellison, DW, Finkelstein, D, Ganguly, D, Du, Z, Sims, M, Yang, C, Interiano, RB, Davidoff, AM & Pfeffer, L 2015, 'Molecular heterogeneity in a patient-derived glioblastoma xenoline is regulated by different cancer stem cell populations', PLoS ONE, vol. 10, no. 5, e0125838. https://doi.org/10.1371/journal.pone.0125838
Garner, Jo Meagan ; Ellison, David W. ; Finkelstein, David ; Ganguly, Debolina ; Du, Ziyun ; Sims, Michelle ; Yang, Chuan ; Interiano, Rodrigo B. ; Davidoff, Andrew M. ; Pfeffer, Lawrence. / Molecular heterogeneity in a patient-derived glioblastoma xenoline is regulated by different cancer stem cell populations. In: PLoS ONE. 2015 ; Vol. 10, No. 5.
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