PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo

R. Auvergne, C. Wu, A. Connell, S. Au, A. Cornwell, M. Osipovitch, A. Benraiss, S. Dangelmajer, H. Guerrero-Cazares, A. Quinones-Hinojosa, S. A. Goldman

Research output: Contribution to journalArticle

Abstract

Glioblastoma (GBM) remains the most common and lethal intracranial tumor. In a comparison of gene expression by A2B5-defined tumor-initiating progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain, we found that the F2R gene encoding PAR1 was differentially overexpressed by A2B5-sorted TPCs isolated from gliomas at all stages of malignant development. In this study, we asked if PAR1 is causally associated with glioma progression. Lentiviral knockdown of PAR1 inhibited the expansion and self-renewal of human GBM-derived A2B5+ TPCs in vitro, while pharmacological inhibition of PAR 1 similarly slowed both the growth and migration of A2B5+ TPCs in culture. In addition, PAR1 silencing potently suppressed tumor expansion in vivo, and significantly prolonged the survival of mice following intracranial transplantation of human TPCs. These data strongly suggest the importance of PAR1 to the self-renewal and tumorigenicity of A2B5-defined glioma TPCs; as such, the abrogation of PAR1-dependent signaling pathways may prove a promising strategy for gliomas.Oncogene advance online publication, 30 November 2015; doi:10.1038/onc.2015.452.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Nov 30 2015

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Neoplastic Stem Cells
Glioma
Stem Cells
Growth
Glioblastoma
Oncogenes
Neuroglia
Publications
Neoplasms
Cell Culture Techniques
Transplantation
Pharmacology
Gene Expression
Brain
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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Auvergne, R., Wu, C., Connell, A., Au, S., Cornwell, A., Osipovitch, M., ... Goldman, S. A. (Accepted/In press). PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo. Oncogene. https://doi.org/10.1038/onc.2015.452

PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo. / Auvergne, R.; Wu, C.; Connell, A.; Au, S.; Cornwell, A.; Osipovitch, M.; Benraiss, A.; Dangelmajer, S.; Guerrero-Cazares, H.; Quinones-Hinojosa, A.; Goldman, S. A.

In: Oncogene, 30.11.2015.

Research output: Contribution to journalArticle

Auvergne, R, Wu, C, Connell, A, Au, S, Cornwell, A, Osipovitch, M, Benraiss, A, Dangelmajer, S, Guerrero-Cazares, H, Quinones-Hinojosa, A & Goldman, SA 2015, 'PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo', Oncogene. https://doi.org/10.1038/onc.2015.452
Auvergne, R. ; Wu, C. ; Connell, A. ; Au, S. ; Cornwell, A. ; Osipovitch, M. ; Benraiss, A. ; Dangelmajer, S. ; Guerrero-Cazares, H. ; Quinones-Hinojosa, A. ; Goldman, S. A. / PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo. In: Oncogene. 2015.
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