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      mTOR inhibition decreases SOX2-SOX9 mediated glioma stem cell activity and temozolomide resistance

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          ABSTRACT

          Background: SOX2 and SOX9 are commonly overexpressed in glioblastoma, and regulate the activity of glioma stem cells (GSCs). Their specific and overlapping roles in GSCs and glioma treatment remain unclear.

          Methods: SOX2 and SOX9 levels were examined in human biopsies. Gain and loss of function determined the impact of altering SOX2 and SOX9 on cell proliferation, senescence, stem cell activity, tumorigenesis and chemoresistance.

          Results: SOX2 and SOX9 expression correlates positively in glioma cells and glioblastoma biopsies. High levels of SOX2 bypass cellular senescence and promote resistance to temozolomide. Mechanistic investigations revealed that SOX2 acts upstream of SOX9. mTOR genetic and pharmacologic (rapamycin) inhibition decreased SOX2 and SOX9 expression, and reversed chemoresistance.

          Conclusions: Our findings reveal SOX2-SOX9 as an oncogenic axis that regulates stem cell properties and chemoresistance. We identify that rapamycin abrogate SOX protein expression and provide evidence that a combination of rapamycin and temozolomide inhibits tumor growth in cells with high SOX2/SOX9.

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          A restricted cell population propagates glioblastoma growth following chemotherapy

          Jian Chen, Yanjiao Li, Tzong-Shiue Yu … (2012)
          Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, with a median survival of about one year 1 . This poor prognosis is due to therapeutic resistance and tumor recurrence following surgical removal. Precisely how recurrence occurs is unknown. Using a genetically-engineered mouse model of glioma, we identify a subset of endogenous tumor cells that are the source of new tumor cells after the drug, temozolomide (TMZ), is administered to transiently arrest tumor growth. A Nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumor cells. Upon arrest of tumor cell proliferation with TMZ, pulse-chase experiments demonstrate a tumor re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumor growth and combined TMZ-ganciclovir treatment impeded tumor development. These data indicate the existence of a relatively quiescent subset of endogenous glioma cells that are responsible for sustaining long-term tumor growth through the production of transient populations of highly proliferative cells.
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            Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells.

            Mario L Suvà, Esther Rheinbay, Shawn M Gillespie … (2014)
            Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on cellular hierarchies reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor-propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, and OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements and are sufficient to fully reprogram differentiated GBM cells to "induced" TPCs, recapitulating the epigenetic landscape and phenotype of native TPCs. We reconstruct a network model that highlights critical interactions and identifies candidate therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in GBM, provides detailed insight into underlying gene regulatory programs, and suggests attendant therapeutic strategies. PAPERCLIP: Copyright © 2014 Elsevier Inc. All rights reserved.
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              SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity.

              Rosaria Gangemi, Fabrizio Griffero, Daniela Marubbi … (2009)
              Glioblastoma, the most aggressive cerebral tumor, is invariably lethal. Glioblastoma cells express several genes typical of normal neural stem cells. One of them, SOX2, is a master gene involved in sustaining self-renewal of several stem cells, in particular neural stem cells. To investigate its role in the aberrant growth of glioblastoma, we silenced SOX2 in freshly derived glioblastoma tumor-initiating cells (TICs). Our results indicate that SOX2 silenced glioblastoma TICs, despite the many mutations they have accumulated, stop proliferating and lose tumorigenicity in immunodeficient mice. SOX2 is then also fundamental for maintenance of the self-renewal capacity of neural stem cells when they have acquired cancer properties. SOX2, or its immediate downstream effectors, would then be an ideal target for glioblastoma therapy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Expert Opin Ther Targets
                Journal ID (iso-abbrev): Expert Opin. Ther. Targets
                Journal ID (archive): IETT
                Journal ID (publisher-id): iett20
                Title: Expert Opinion on Therapeutic Targets
                Publisher: Taylor & Francis
                ISSN (Print): 1472-8222
                ISSN (Electronic): 1744-7631
                Publication date (Print): 2 April 2016
                Publication date (Electronic): 23 February 2016
                Volume: 20
                Issue: 4
                Pages: 393-405
                Affiliations
                [ a ]Cellular Oncology group, Biodonostia Institute , San Sebastian, Spain
                [ b ]Neuro-Oncology Committee, Donostia Hospital , San Sebastian, Spain
                [ c ]Stem Cell Biology and Developmental Genetics laboratory, The Francis Crick Institute , London, UK
                [ d ]Neural Stem Cells and Brain Cancer group, MRC Centre for Regenerative Medicine , Edinburgh, UK
                [ e ]IKERBASQUE, Basque Foundation for Science , Bilbao, Spain
                Author notes
                CONTACT Ander Matheu ander.matheu@ 123456biodonostia.org Biodonostia Institute , Paseo Dr. Beguiristain s/n, E-20014 San Sebastian, Spain
                [* ]

                These authors contributed equally to this work.

                Article
                Publisher ID: 1151002
                DOI: 10.1517/14728222.2016.1151002
                PMC ID: 4898154
                PubMed ID: 26878385
                SO-VID: 80c83462-cab8-4998-a180-a6b7e51544c6
                Copyright © © 2016 The Author(s). Published by Taylor & Francis.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

                History
                Date received : 27 May 2015
                Date accepted : 2 February 2016
                Page count
                Figures: 5, References: 47, Pages: 13
                Funding
                Funded by: Association for International Cancer Research 10.13039/501100000391
                Award ID: 13-1270
                Categories
                Subject: Article
                Subject: Original Research

                Keywords: glioma stem cell,sox2,sox9,senescence,rapamycin and temozolomide
                Data availability:
                Keywords: glioma stem cell, sox2, sox9, senescence, rapamycin and temozolomide

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