Methylation-dependent Tissue Factor Suppression Contributes to the Reduced Malignancy of IDH1-mutant Gliomas

Dusten Unruh, Snezana Mirkov, Brian Wray, Michael Drumm, Jonathan Lamano, Yuping D. Li, Qazi F. Haider, Rodrigo Javier, Kathleen McCortney, Amanda Saratsis, Denise M. Scholtens, Jann N. Sarkaria, C. David James, Craig Horbinski

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Purpose: Gliomas with isocitrate dehydrogenase 1 mutations (IDH1 mut ) are less aggressive than IDH1 wild-type (IDH1 wt ) gliomas and have global genomic hypermethylation. Yet it is unclear how specific hypermethylation events contribute to the IDH1 mut phenotype. Previously, we showed that the gene encoding the procoagulant tissue factor (TF), F3, is among the most hypermethylated and downregulated genes in IDH1 mut gliomas, correlating with greatly reduced thrombosis in patients with IDH1 mut glioma. Because TF also increases the aggressiveness of many cancers, the current study explored the contribution of TF suppression to the reduced malignancy of IDH1 mut gliomas. Experimental Design: TF expression was manipulated in patient-derived IDH1 mut and IDH1 wt glioma cells, followed by evaluation of in vitro and in vivo behavior and analyses of cell signaling pathways. Results: A demethylating agent, decitabine, increased F3 transcription and TF-dependent coagulative activity in IDH1 mut cells, but not in IDH1 wt cells. TF induction enhanced the proliferation, invasion, and colony formation of IDH1 mut cells, and increased the intracranial engraftment of IDH1 mut GBM164 from 0% to 100% (P ¼ 0.0001). Conversely, TF knockdown doubled the median survival of mice engrafted with IDH1 wt /EGFRvIII amp GBM6, and caused complete regression of IDH1 wt /EGFR amp GBM12 (P ¼ 0.001). In vitro and in vivo effects were linked to activation of receptor tyrosine kinases (RTK) by TF through a Src-dependent intracellular pathway, even when extracellular RTK stimulation was blocked. TF stimulated invasion predominately through upregulation of b-catenin. Conclusions: These data show that TF suppression is a component of IDH1 mut glioma behavior, and that it may therefore be an attractive target against IDH1 wt gliomas.

Original languageEnglish (US)
Pages (from-to)747-759
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number2
DOIs
StatePublished - Jan 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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