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Expression Profiling of the MAP Kinase Phosphatase Family Reveals a Role for DUSP1 in the Glioblastoma Stem Cell Niche

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Cancer Microenvironment

Abstract

The dual specificity phosphatases (DUSPs) constitute a family of stress-induced enzymes that provide feedback inhibition on mitogen-activated protein kinases (MAPKs) critical in key aspects of oncogenic signaling. While described in other tumor types, the landscape of DUSP mRNA expression in glioblastoma (GB) remains largely unexplored. Interrogation of the REpository for Molecular BRAin Neoplasia DaTa (REMBRANDT) revealed induction (DUSP4, DUSP6), repression (DUSP2, DUSP7–9), or mixed (DUSP1, DUSP5, DUSP10, DUSP15) DUSP transcription of select DUSPs in bulk tumor specimens. To resolve features specific to the tumor microenvironment, we searched the Ivy Glioblastoma Atlas Project (Ivy GAP) repository, which highlight DUSP1, DUSP5, and DUSP6 as the predominant family members induced within pseudopalisading and perinecrotic regions. The inducibility of DUSP1 in response to hypoxia, dexamethasone, or the chemotherapeutic agent camptothecin was confirmed in GB cell lines and tumor-derived stem cells (TSCs). Moreover, we show that loss of DUSP1 expression is a characteristic of TSCs and correlates with expression of tumor stem cell markers in situ (ABCG2, PROM1, L1CAM, NANOG, SOX2). This work reveals a dynamic pattern of DUSP expression within the tumor microenvironment that reflects the cumulative effects of factors including regional ischemia, chemotherapeutic exposure among others. Moreover, our observation regarding DUSP1 dysregulation within the stem cell niche argue for its importance in the survival and proliferation of this therapeutically resistant population.

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Abbreviations

DUSP1:

Dual specificity phosphatase 1

GB:

Glioblastoma

TSC:

Tumor stem cell

DEX:

Dexamethasone

CPT:

Camptothecin

LE:

Leading edge

CT:

Bulk cellular tumor

CTpan:

Cellular tumor pseudopalisading around necrosis

CTpnz:

Cellular tumor perinecrotic zone

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Acknowledgments

This project was funded by awards from the National Institutes of Health to Marc W. Halterman (R01-NS076617) and Bradley N. Mills (F31-CA180358).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA

    Bradley N. Mills

  2. Center for Neurotherapeutics Discovery, University of Rochester Medical Center, 601 Elmwood Avenue, Box 645, Rochester, NY, 14642, USA

    Bradley N. Mills, George P. Albert & Marc W. Halterman

  3. Department of Neurology, University of Rochester Medical Center, Rochester, NY, 14642, USA

    Marc W. Halterman

  4. Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, 14642, USA

    Marc W. Halterman

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  1. Bradley N. Mills
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  2. George P. Albert
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Corresponding author

Correspondence to Marc W. Halterman.

Electronic supplementary material

Fig. S1

Characterization of GB TSC differentiation. Flow cytometry contour plots (a) and geometric mean histogram representations (b) of primitive TSCs (red) and 3-day serum-differentiated dTSCs (blue) for expression of the stem cell marker SOX2, mature glial marker GLAST1, and mature neuronal marker NEUROD1 (n = 1). (GIF 132 kb)

High resolution image (EPS 2128 kb)

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Mills, B.N., Albert, G.P. & Halterman, M.W. Expression Profiling of the MAP Kinase Phosphatase Family Reveals a Role for DUSP1 in the Glioblastoma Stem Cell Niche. Cancer Microenvironment 10, 57–68 (2017). https://doi.org/10.1007/s12307-017-0197-6

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  • DOI: https://doi.org/10.1007/s12307-017-0197-6

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