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Methylation-Dependent Tissue Factor Suppression Contributes to the Reduced Malignancy of IDH1 Mutant Gliomas

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Methylation-Dependent Tissue Factor Suppression Contributes to the Reduced Malignancy of IDH1 Mutant Gliomas Author Manuscript Published OnlineFirst on September 28, 2018; DOI: 10.1158/1078-0432.CCR-18-1222 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Unruh et al. Methylation-dependent Tissue Factor suppression contributes to the reduced malignancy of IDH1 mutant gliomas 1 1 2 1 1 Dusten Unruh, Snezana Mirkov, Brian Wray, Michael Drumm, Jonathan Lamano, Yuping D Li,1 Qazi F. Haider,1 Rodrigo Javier,1 Kathleen McCortney,1 Amanda Saratsis,1 Denise M. Scholtens,3 Jann N. Sarkaria,4 C. David James,1 Craig Horbinski1,5 1Department of Neurological Surgery, Northwestern University, Chicago, IL, 60611, USA 2Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, 60611, USA 3Department of Preventive Medicine, Northwestern University, Chicago, IL, 60611, USA 4Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 55905, USA 5Department of Pathology, Northwestern University, Chicago, IL, 60611, USA RUNNING TITLE Tissue Factor in IDH1mut and IDH1wt gliomas KEYWORDS Tissue Factor; glioma; isocitrate dehydrogenase; beta-catenin; protease-activated receptor FINANCIAL SUPPORT This work was supported by NIH grants K08CA155764 and R01NS102669 (C.H.). D.U. was supported by NIH grants T32CA070085 and F32CA216996. C.H., D.M.S., and C.D.J. were also supported by the Northwestern SPORE in Brain Cancer P50CA221747. The Mayo Clinic Brain Tumor Patient-Derived Xenograft National Resource is supported by Mayo Clinic, the Mayo SPORE in Brain Cancer P50CA108961 and NIH grant R24NS92940. Histology and fluorescent 1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 28, 2018; DOI: 10.1158/1078-0432.CCR-18-1222 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Unruh et al. microscopy services were provided by the Mouse Histology and Phenotyping Laboratory and the Center for Advanced Microscopy/Nikon Imaging Center, respectively; both are supported by NCI P30CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. CORRESPONDING AUTHOR Craig Horbinski, M.D., Ph.D., Northwestern University Tarry 2-705 300 East Superior St. Chicago, IL 60611 Phone: 312-503-6127 Email: [email protected] CONFLICTS OF INTEREST The authors disclose no potential conflicts of interest 2 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 28, 2018; DOI: 10.1158/1078-0432.CCR-18-1222 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Unruh et al. TRANSLATIONAL RELEVANCE IDH1mut gliomas are much less aggressive than IDH1wt gliomas, though it is still not fully understood why. We recently discovered that IDH1mut gliomas produce far less TF than IDH1wt gliomas. TF is well known for triggering blood coagulation, but it also promotes malignant behavior via activation of protease-activated receptor 2 (PAR2). Using patient-derived IDH1wt and IDH1mut glioma xenografts, this work (i) defines a mechanism for TF suppression in IDH1mut gliomas; (ii) advances our understanding of how TF-PAR2 signaling contributes to glioma malignancy; (iii) describes a novel mechanism for cancer resistance to receptor tyrosine kinase inhibitors; (iv) sheds light on why it is so difficult to develop patient-derived models of IDH1mut gliomas; (v) identifies a new therapeutic target for treating IDH1wt gliomas. 3 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 28, 2018; DOI: 10.1158/1078-0432.CCR-18-1222 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Unruh et al. ABSTRACT Purpose: Gliomas with isocitrate dehydrogenase 1 mutations (IDH1mut) are less aggressive than IDH1 wild-type (IDH1wt) gliomas and have global genomic hypermethylation. Yet it is unclear how specific hypermethylation events contribute to the IDH1mut phenotype. Previously, we showed that the gene encoding the procoagulant Tissue Factor (TF), F3, is among the most hypermethylated and downregulated genes in IDH1mut gliomas, correlating with greatly reduced thrombosis in IDH1mut glioma patients. Because TF also increases the aggressiveness of many cancers, the current study explored the contribution of TF suppression to the reduced malignancy of IDH1mut gliomas. Experimental Design: TF expression was manipulated in patient-derived IDH1mut and IDH1wt 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 IDH1mut cells, but not in IDH1wt cells. TF induction enhanced the proliferation, invasion, and colony formation of IDH1mut cells, and increased the intracranial engraftment of IDH1mut GBM164 from 0% to 100% (P=0.0001). Conversely, TF knockdown doubled the median survival of mice engrafted with IDH1wt/EGFRvIIIamp GBM6, and caused complete regression of IDH1wt/EGFRamp GBM12 (P=0.001). In vitro and in vivo effects were linked to activation of receptor tyrosine kinases (RTKs) by TF through a Src-dependent intracellular pathway, even when extracellular RTK stimulation was blocked. TF stimulated invasion predominately through upregulation of β-catenin. Conclusions: These data show that TF suppression is a component of IDH1mut glioma behavior, and that it may therefore be an attractive target against IDH1wt gliomas. 4 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 28, 2018; DOI: 10.1158/1078-0432.CCR-18-1222 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Unruh et al. INTRODUCTION Approximately 20-30% of diffusely infiltrative gliomas contain point mutations in the metabolic enzyme isocitrate dehydrogenase 1 or, less commonly, IDH2 (hereafter collectively referred to as “IDH1mut”) (1). These mutations unmask latent oxidoreductase activities, causing α-ketoglutarate to be converted into D-2-hydroxyglutarate (D2HG) (2). The D2HG product of IDH1mut competitively inhibits many α-ketoglutarate-dependent DNA and histone demethylases, resulting in genomic hypermethylation and altered transcription of many genes (3,4). Although IDH1mut has been linked to suppression of cellular differentiation and predisposition toward oncogenic transformation, it is also associated with lower World Health Organization (WHO) grade and longer survival in glioma patients (5-7). As further indication of their attenuated malignancy, IDH1mut gliomas are much more difficult to grow in culture or as patient-derived xenografts (PDX), relative to IDH1wt gliomas (8,9). The basis for the lesser malignancy of IDH1mut tumors is far from fully understood. Previously, we reported that the absence of intratumoral microthrombi is the best histologic predictor of IDH1mut in gliomas, independent of WHO grade and patient age (10). We also found that IDH1mut gliomas are far less likely to cause systemic venous thromboemboli (VTE) than IDH1wt gliomas, again independent of WHO grade and patient age. Further investigation into the mechanistic underpinnings for these clinically-based observations revealed that F3, the gene encoding Tissue Factor (TF), is one of the most hypermethylated and downregulated genes in IDH1mut gliomas (10). TF is a highly conserved glycoprotein that binds with activated Coagulation Factor VII (FVIIa) to initiate the clotting cascade, and its production and release by cancers into the systemic circulation have been repeatedly linked to VTE in patients (11). Circulating TF is lower in patients with IDH1mut gliomas than IDH1wt gliomas, and elevated plasma TF positively correlates with increased risk of glioma-induced VTE (10). In addition to its procoagulant activity, the TF-FVIIa complex can also activate transmembrane G protein-coupled protease-activated receptors (PARs), especially PAR2 (12). 5 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 28, 2018; DOI: 10.1158/1078-0432.CCR-18-1222 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Unruh et al. TF-PAR2 activity is important for wound healing at sites of vascular injury and hemostasis. In cancer, however, TF-PAR2 initiates signaling cascades that promote growth, angiogenesis, invasion, and metastasis (13). An unbiased screen for metastatic enhancer elements found that TF was a major contributor to tumor metastasis (14). Less is known about the activity of TF in gliomas, although it has been shown to increase malignant phenotypes when ectopically expressed in glioblastoma (GBM) cell lines (15-17). Our prior work showed that, in patients with IDH1wt GBM, high intratumoral TF protein expression correlated with an approximately 50% reduction in median survival (10). Therefore, we hypothesized that TF enhances the malignancy of IDH1wt gliomas, and that its suppression is an important component of the less aggressive IDH1mut glioma phenotype. 6 Downloaded from clincancerres.aacrjournals.org
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