Shideng Bao

Case Western Reserve University, Cleveland, Ohio, United States

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Publications (60)646.49 Total impact

  • J.S. Yu · J. Man · J. Shoemake · S. Bao · Q. Wu · J. Rich ·

    International journal of radiation oncology, biology, physics 11/2015; 93(3):S184. DOI:10.1016/j.ijrobp.2015.07.441 · 4.26 Impact Factor
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    ABSTRACT: Glioblastoma multiforme (GBM) is the most lethal brain tumor. Tumor relapse in GBM is inevitable despite maximal therapeutic interventions. Glioma stem cells (GSCs) have been found to be critical players in therapeutic resistance and tumor recurrence. Therapeutic drugs targeting GSCs may significantly improve GBM treatment. In this study, we demonstrated that arsenic trioxide (As2O3) effectively disrupted GSCs and inhibited tumor growth in the GSC-derived orthotopic xenografts by targeting the promyelocytic leukaemia (PML). As2O3 treatment induced rapid degradation of PML protein along with severe apoptosis in GSCs. Disruption of the endogenous PML recapitulated the inhibitory effects of As2O3 treatment on GSCs both in vitro and in orthotopic tumors. Importantly, As2O3 treatment dramatically reduced GSC population in the intracranial GBM xenografts and increased the survival of mice bearing the tumors. In addition, As2O3 treatment preferentially inhibited cell growth of GSCs but not matched non-stem tumor cells (NSTCs). Furthermore, As2O3 treatment or PML disruption potently diminished c-Myc protein levels through increased poly-ubiquitination and proteasome degradation of c-Myc. Our study indicated a potential implication of As2O3 in GBM treatment and highlighted the important role of PML/c-Myc axis in the maintenance of GSCs.
    Oncotarget 10/2015; DOI:10.18632/oncotarget.5836 · 6.36 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):4178-4178. DOI:10.1158/1538-7445.AM2015-4178 · 9.33 Impact Factor
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    ABSTRACT: Glioblastoma is the most prevalent and lethal primary intrinsic brain tumor. Glioblastoma displays hierarchical arrangement with a population of self-renewing and tumorigenic glioma tumor initiating cells (TICs), or cancer stem cells. While non-neoplastic neural stem cells are generally quiescent, glioblastoma TICs are often proliferative with mitotic control offering a potential point of fragility. Here, we interrogate the role of cell-division cycle protein 20 (CDC20), an essential activator of anaphase-promoting complex (APC) E3 ubiquitination ligase, in the maintenance of TICs. By chromatin analysis and immunoblotting, CDC20 was preferentially expressed in TICs relative to matched non-TICs. Targeting CDC20 expression by RNA interference attenuated TIC proliferation, self-renewal and in vivo tumor growth. CDC20 disruption mediated its effects through induction of apoptosis and inhibition of cell cycle progression. CDC20 maintains TICs through degradation of p21CIP1/WAF1, a critical negative regulator of TICs. Inhibiting CDC20 stabilized p21CIP1/WAF1, resulting in repression of several genes critical to tumor growth and survival, including CDC25C, c-Myc and Survivin. Transcriptional control of CDC20 is mediated by FOXM1, a central transcription factor in TICs. These results suggest CDC20 is a critical regulator of TIC proliferation and survival, linking two key TIC nodes - FOXM1 and p21CIP1/WAF1 - elucidating a potential point for therapeutic intervention.
    Oncotarget 04/2015; 6(15). DOI:10.18632/oncotarget.3676 · 6.36 Impact Factor
  • M Rivera · Q Wu · P Hamerlik · A B Hjelmeland · S Bao · J N Rich ·
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    ABSTRACT: Glioblastoma (GBM), the most prevalent type of primary intrinsic brain cancer in adults, remains universally fatal despite maximal therapy, including radiotherapy and chemotherapy. Cytotoxic therapy generates double-stranded DNA breaks (DSBs), most commonly repaired by homologous recombination (HR). We hypothesized that cancer cells coopt meiotic repair machinery as DSBs are generated during meiosis and repaired by molecular complexes distinct from genotoxic responses in somatic tissues. Indeed, we found that gliomas express meiotic repair genes and their expression informed poor prognosis. We interrogated the function of disrupted meiotic cDNA1 (DMC1), a homolog of RAD51, the primary recombinase used in mitotic cells to search and recombine with the homologous DNA template. DMC1, whose only known function is as an HR recombinase, was expressed by GBM cells and induced by radiation. Although targeting DMC1 in non-neoplastic cells minimally altered cell growth, DMC1 depletion in GBM cells decreased proliferation, induced activation of CHK1 and expression of p21(CIP1/WAF1), and increased RPA foci, suggesting increased replication stress. Combining loss of DMC1 with ionizing radiation inhibited activation of DNA damage responses and increased radiosensitivity. Furthermore, loss of DMC1 reduced tumor growth and prolonged survival in vivo. Our results suggest that cancers coopt meiotic genes to augment survival under genotoxic stress, offering molecular targets with high therapeutic indices.
    Cell Death & Disease 04/2015; 6(4):e1732. DOI:10.1038/cddis.2015.75 · 5.01 Impact Factor
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    ABSTRACT: Brain tumor initiating cells (BTICs) co-opt the neuronal high affinity glucose transporter, GLUT3, to withstand metabolic stress. We investigated another mechanism critical to brain metabolism, mitochondrial morphology, in BTICs. BTIC mitochondria were fragmented relative to non-BTIC tumor cell mitochondria, suggesting that BTICs increase mitochondrial fission. The essential mediator of mitochondrial fission, dynamin-related protein 1 (DRP1), showed activating phosphorylation in BTICs and inhibitory phosphorylation in non-BTIC tumor cells. Targeting DRP1 using RNA interference or pharmacologic inhibition induced BTIC apoptosis and inhibited tumor growth. Downstream, DRP1 activity regulated the essential metabolic stress sensor, AMP-activated protein kinase (AMPK), and targeting AMPK rescued the effects of DRP1 disruption. Cyclin-dependent kinase 5 (CDK5) phosphorylated DRP1 to increase its activity in BTICs, whereas Ca(2+)-calmodulin-dependent protein kinase 2 (CAMK2) inhibited DRP1 in non-BTIC tumor cells, suggesting that tumor cell differentiation induces a regulatory switch in mitochondrial morphology. DRP1 activation correlated with poor prognosis in glioblastoma, suggesting that mitochondrial dynamics may represent a therapeutic target for BTICs.
    Nature Neuroscience 03/2015; 18(4). DOI:10.1038/nn.3960 · 16.10 Impact Factor
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    ABSTRACT: Glioma stem-like cells (GSCs) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells and it is re-emerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 02/2015; 75(8). DOI:10.1158/0008-5472.CAN-14-3621 · 9.33 Impact Factor
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    ABSTRACT: Tumour-associated macrophages (TAMs) are enriched in glioblastoma multiformes (GBMs) that contain glioma stem cells (GSCs) at the apex of their cellular hierarchy. The correlation between TAM density and glioma grade suggests a supportive role for TAMs in tumour progression. Here we interrogated the molecular link between GSCs and TAM recruitment in GBMs and demonstrated that GSCs secrete periostin (POSTN) to recruit TAMs. TAM density correlates with POSTN levels in human GBMs. Silencing POSTN in GSCs markedly reduced TAM density, inhibited tumour growth, and increased survival of mice bearing GSC-derived xenografts. We found that TAMs in GBMs are not brain-resident microglia, but mainly monocyte-derived macrophages from peripheral blood. Disrupting POSTN specifically attenuated the tumour-supportive M2 type of TAMs in xenografts. POSTN recruits TAMs through the integrin αvβ3 as blocking this signalling by an RGD peptide inhibited TAM recruitment. Our findings highlight the possibility of improving GBM treatment by targeting POSTN-mediated TAM recruitment.
    Nature Cell Biology 01/2015; 17(2). DOI:10.1038/ncb3090 · 19.68 Impact Factor
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    ABSTRACT: Different cancer cell compartments often communicate through soluble factors to facilitate tumor growth. Glioma stem cells (GSCs) are a subset of tumor cells that resist standard therapy to contribute to disease progression. How GSCs employ a distinct secretory program to communicate with and nurture each other over the nonstem tumor cell (NSTC) population is not well defined. Here, we show that GSCs preferentially secrete Sema3C and coordinately express PlexinA2/D1 receptors to activate Rac1/nuclear factor (NF)-κB signaling in an autocrine/paracrine loop to promote their own survival. Importantly, Sema3C is not expressed in neural progenitor cells (NPCs) or NSTCs. Disruption of Sema3C induced apoptosis of GSCs, but not NPCs or NSTCs, and suppressed tumor growth in orthotopic models of glioblastoma. Introduction of activated Rac1 rescued the Sema3C knockdown phenotype in vivo. Our study supports the targeting of Sema3C to break this GSC-specific autocrine/paracrine loop in order to improve glioblastoma treatment, potentially with a high therapeutic index. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 11/2014; 9(5). DOI:10.1016/j.celrep.2014.10.055 · 8.36 Impact Factor
  • Qi Xie · William A Flavahan · Shideng Bao · Jeremy Rich ·
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    ABSTRACT: In this issue of Cell Stem Cell, Zhu et al. (2014) demonstrate that a genetically engineered glioma model displays a functional cellular hierarchy defined by expression of the nuclear orphan receptor Tlx. Targeting cancer stem cells through genetic deletion of TLX promotes cancer stem cell death and differentiation and extends survival.
    Cell Stem Cell 08/2014; 15(2):114-116. DOI:10.1016/j.stem.2014.07.004 · 22.27 Impact Factor
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    ABSTRACT: Glioblastomas are highly lethal brain tumors containing tumor-propagating glioma stem cells (GSCs). The molecular mechanisms underlying the maintenance of the GSC phenotype are not fully defined. Here we demonstrate that the zinc finger and X-linked transcription factor (ZFX) maintains GSC self-renewal and tumorigenic potential by up-regulating c-Myc expression. ZFX is differentially expressed in GSCs relative to non-stem glioma cells and neural progenitor cells (NPCs). Disrupting ZFX by shRNA reduced c-Myc expression and potently inhibited GSC self-renewal and tumor growth. Ectopic expression of c-Myc to its endogenous level rescued the effects caused by ZFX disruption, supporting that ZFX controls GSC properties through c-Myc. Furthermore, ZFX binds to a specific sequence (GGGCCCCG) on the human c-Myc promoter to up-regulate c-Myc expression. These data demonstrate that ZFX functions as a critical upstream regulator of c-Myc and plays essential roles in the maintenance of the GSC phenotype. This study also supports that c-Myc is a dominant driver linking self-renewal to malignancy. Stem Cells 2014
    Stem Cells 08/2014; 32(8). DOI:10.1002/stem.1730 · 6.52 Impact Factor
  • Shideng Bao · Lin Cheng · Zhi Huang · Wenchao Zhou · Qiulian Wu · Jeremy N Rich ·
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    ABSTRACT: Glioblastoma (GBM) is the most lethal type of primary brain tumor with florid angiogenesis. GBMs display striking cellular hierarchies containing self-renewing glioma stem cells (GSCs) that are highly tumorigenic. GSCs not only produce elevated levels of VEGF to promote tumor angiogenesis but also contribute to cellular compartments of tumor vessels.
    Neuro-Oncology 07/2014; 16 Suppl 3:iii14. DOI:10.1093/neuonc/nou206.50 · 5.56 Impact Factor

  • Neuro-Oncology 07/2014; 16 Suppl 3:iii36. DOI:10.1093/neuonc/nou208.49 · 5.56 Impact Factor
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    Wenchao Zhou · Shideng Bao ·
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    ABSTRACT: Glioblastoma multiforme (GBM) is the most lethal and aggressive type of primary brain malignancy. Failures of the traditional therapies in treating GBMs raise the urgent requirement to develop new approaches with more responsive targets. The phenomenon of the high infiltration of tumor-associated macrophages (TAMs) into GBMs has been observed for a long time. Regardless of the limited knowledge about TAMs, the high percentage of supportive TAM in GBM tumor mass makes it possible to be a good target for GBM treatment. In this review, we discussed the unique features of TAMs in GBMs, including their origin, the tumor-supportive properties, the secreted cytokines, and the relevant mechanisms. In addition, we tried to interpret the current understandings about the interplay between GBM cancer cells and TAMs. Finally, the translational studies of targeting TAMs were also described.
    Cancers 06/2014; 6(2):723-40. DOI:10.3390/cancers6020723
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    ABSTRACT: Stem cells reside in niches that regulate the balance between self-renewal and differentiation. The identity of a stem cell is linked with the ability to interact with its niche through adhesion mechanisms. To identify targets that disrupt cancer stem cell (CSC) adhesion, we performed a flow cytometry screen on patient-derived glioblastoma (GBM) cells and identified junctional adhesion molecule A (JAM-A) as a CSC adhesion mechanism essential for self-renewal and tumor growth. JAM-A was dispensable for normal neural stem/progenitor cell (NPC) function, and JAM-A expression was reduced in normal brain versus GBM. Targeting JAM-A compromised the self-renewal of CSCs. JAM-A expression negatively correlated to GBM patient prognosis. Our results demonstrate that GBM-targeting strategies can be identified through screening adhesion receptors and JAM-A represents a mechanism for niche-driven CSC maintenance.
    Cell Reports 12/2013; 6(1). DOI:10.1016/j.celrep.2013.11.043 · 8.36 Impact Factor
  • David L Schonberg · Shideng Bao · Jeremy N Rich ·
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    ABSTRACT: Identifying genomic alterations in cancer does not guarantee therapeutic benefit. A new study combining DNA and RNA sequencing with functional validation uncovers new genetic driver alterations in glioblastoma with potential for clinical translation.
    Nature Genetics 09/2013; 45(10):1105-7. DOI:10.1038/ng.2775 · 29.35 Impact Factor

  • Cancer Research 04/2013; 73(8 Supplement):3898-3898. DOI:10.1158/1538-7445.AM2013-3898 · 9.33 Impact Factor
  • W Zhou · S Bao ·
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    ABSTRACT: The promyelocytic leukemia (PML) protein, initially discovered as a part of the PML/retinoic acid receptor alpha fusion protein, has been found to be a critical player in oncogenesis and tumor progression. Multiple cellular activities, including DNA repair, alternative lengthening of telomeres, transcriptional control, apoptosis and senescence, are regulated by PML and its featured subcellular structure, the PML nuclear body. In correspondence with its role in many important life processes, PML mediates several complex downstream signaling pathways. The determinant function of PML in tumorigenesis and cancer progression raises the interest in its involvement in cancer stem cells (CSCs), a subpopulation of cancer cells that share properties with stem cells and are critical for tumor propagation. Recently, there are exciting discoveries concerning the requirement of PML in CSC maintenance. Growing evidences strongly suggest a positive role of PML in regulating CSCs in both hematopoietic cancers and solid tumors, whereas the underlying mechanisms may be different and remain elusive. Here we summarize and discuss the PML-mediated signaling pathways in cancers and their potential roles in regulating CSCs.Oncogene advance online publication, 8 April 2013; doi:10.1038/onc.2013.111.
    Oncogene 04/2013; 33(12). DOI:10.1038/onc.2013.111 · 8.46 Impact Factor
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    ABSTRACT: Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived pericytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM specimens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothelial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor β. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic targeting of GSC-derived pericytes may effectively block tumor progression and improve antiangiogenic therapy.
    Cell 03/2013; 153(1):139-52. DOI:10.1016/j.cell.2013.02.021 · 32.24 Impact Factor

Publication Stats

7k Citations
646.49 Total Impact Points


  • 2012-2015
    • Case Western Reserve University
      • Department of Molecular Medicine
      Cleveland, Ohio, United States
  • 2010-2015
    • Lerner Research Institute
      • Department of Cellular and Molecular Medicine
      Cleveland, Ohio, United States
  • 2014
    • Cleveland Clinic
      • Department of Neurosurgery
      Cleveland, Ohio, United States
  • 2004-2009
    • Xiamen University
      • • Key Laboratory of the Ministry of Education For Cell Biology and Tumor Cell Engineering
      • • School of Life Sciences
      Amoy, Fujian, China
  • 2008
    • Duke University
      • Department of Surgery
      Durham, North Carolina, United States
  • 2004-2007
    • Duke University Medical Center
      • • Department of Surgery
      • • Department of Pharmacology and Cancer Biology
      Durham, North Carolina, United States