Shideng Bao Laboratory

Research

Overview

Glioblastoma (GBM)  is the most  common and  lethal type of primary brain tumor with extremely poor prognosis.  GBM displays remarkable cellular heterogeneity and hierarchy containing glioma stem cells (GSCs) with potent tumorigenic potential.  GSCs not only maintain tumor growth but also promote malignant progression.  Our research focuses on the signaling pathways that  control the  stem cell-like property and tumorigenic potential  of  GSCs as well as the molecular interactions between GSCs and the tumor microenvironment (TME) including vascular pericytes and tumor-associated macrophages (TAMs).  Our goal is to develop novel therapeutics targeting GSCs and the interplay between GSCs and the TME to improve GBM treatment. We are working on three major areas:

Therapeutic targeting of  glioma stem cells:  Our previous studies demonstrated that GSCs  promote therapeutic resistance, tumor angiogenesis, cancer invasion and formation of the blood-tumor barrier, suggesting that targeting GSCs may significantly improve GBM treatment. We have identified several GSC-specific druggable targets such as BMX kinase. We are  on the way  to develop new therapeutics  targeting GSCs to effectively improve GBM treatment. Recently, we found that targeting GSCs through BMX inhibition by ibrutinib potently  suppressed GBM tumor growth and significantly synergized with radiotherapy.

Glioma stem cell-derived pericytes and the blood-tumor barrier:  The blood-tumor barrier (BTB) represents a major obstacle to effective drug delivery into GBM tumors. As a filtering barrier of blood vessels, the BTB in GBM prevents most potent anti-cancer drugs from penetrating the tumor, but the blood-brain barrier (BBB) in normal brain protects brain functions by blocking entry of potentially harmful materials. Thus, selective disruption of the BTB but not the BBB is crucial for improving therapeutic efficacy for malignant brain tumors including GBM. We have discovered that GSCs generate the majority of vascular pericytes to  maintain vascular structure and function to promote tumor growth. Recently, we found that selective targeting of GSC-derived pericytes disrupted the BTB tight junctions to enhance drug delivery into GBM tumors and improve chemotherapeutic efficacy. We will continue to elucidate the functional significance of GSC-derived neoplastic pericytes in the BTB formation and maintenance  and develop effective therapeutic approaches to disrupt the BTB. 

Interplay between glioma stem cells and tumor-associated macrophages (TAMs):  Immunotherapy is a promising treatment, but immune evasion in GBM tumors poses a significant challenge to clinical efficacy. The mechanisms underlying the immunosuppression in GBMs are poorly understood.  GBM contains abundant TAMs, but they lack apparent phagocytic activity. The inverse correlation between TAM infiltration and GBM prognosis suggests a supportive role of TAMs in tumor progression. We have interrogated the role of GSCs in TAM recruitment and identified a key molecular link between GSCs and TAM recruitment in GBMs. We  found that GSCs secrete Periostin (POSTN) to recruit monocyte-derived TAMs and maintain M2 TAMs to promote tumor progression. Silencing POSTN in GSCs markedly reduced TAM density, inhibited tumor growth, and increased survival of mice bearing GSC-derived xenografts, highlighting the possibility of improving GBM treatment by targeting POSTN-mediated TAM recruitment.  We will continue to investigate the bi-directional interactions between GSCs and TMAs.  Our goal is to improve immunotherapy by  overcoming the immunosuppressive microenvironment in GBM tumors.

Additional research areas in my lab include cancer stem cell-mediated therapeutic resistance, cancer invasion and tumor metastasis particularly brain metastases of lung cancers.

Selected Publications

1.  Zhai K, Huang Z, Huang Q, Tao W, Fang X, Zhang A, Li X, Stark GR, Hamilton TA, Bao S*. Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells. Nature Cancer 2021; 2:1136-1151.  [Highlighted by several news & views: Cancer Discovery; Nature Cancer; BioArt; Alzforum; BioWorld; etc.] 
2. Fang X, Huang Z, Zhai K, Huang Q, Tao W, Kim L, Wu Q, Almasan A, Yu JS, Li X, Stark GR, Rich JN, Bao S*. Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice. Sci Transl Med. 2021; 13:eabc7275.
3.  Zhang A, Huang Z, Tao W, Zhai K, Wu Q, Rich JN, Zhou W, Bao S*. USP33 deubiquitinates and stabilizes HIF-2alpha to promote hypoxia response in glioma stem cells. EMBO J.  2022; e109187. 
4.  Tao W, Chu C, Zhou W, Huang Z, Zhai K, Fang X, Huang Q, Zhang A, Wang X, Yu X, Huang H, Wu Q, Sloan AE, Yu JS, Li X, Stark GR, Rich JN, Bao S*. Dual Role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma. Nature Commun. 2020; 11(1):3015. 
5.  Dixit D, Prager BC, Gimple RC, Miller TE, Wu Q, Yomtoubian S, Kidwell RL, Lv D, Zhao L, Qiu Z, Zhang G, Lee D, Park DE, Wechsler-Reya RJ, Wang X, Bao S, Rich JN. Glioblastoma stem cells reprogram chromatin in vivo to generate selective therapeutic dependencies on DPY30 and phosphodiesterases. Sci Transl Med. 2022; 14: eabf3917. 
6.  Tao W, Zhang A, Zhai K, Huang Z, Huang H, Zhou W, Huang Q, Fang X, Prager BC, Wang X, Wu Q, Sloan AE, Ahluwalia MS, Lathia JD, Yu JS, Rich JN, Bao S*. SATB2 drives glioblastoma growth by recruiting CBP to promote FOXM1 expression in glioma stem cells. EMBO Mol Med. 2020; 12(12):e12291. 
7.  Zhang A, Tao W, Zhai K, Fang X, Huang Z, Yu JS, Sloan AE, Rich JN, Zhou W, Bao S*. Protein sumoylation with SUMO1 promoted by Pin1 in glioma stem cells augments glioblastoma malignancy. Neuro Oncol. 2020; 22(12): 1809-1821. 
8. Shi Y, Guryanova OA, Zhou W, Liu C, Huang Z, Fang X, Wang X, Chen C, Wu Q, He Z, Wang W, Zhang W, Jiang T, Liu Q, Chen Y, Wang W, Wu J, Kim L, Gimple RC, Feng H, Kung HF, Yu JS, Rich JN, Ping YF, Bian XW, Bao S*. Ibrutinib inactivates BMX-STAT3 in glioma stem cells to impair malignant growth and radioresistance. Sci. Transl. Med.  10: eaah6816; 2018.
9. Zhou W, Chen C, Shi Y, Wu Q, Gimple RC, Fang X, Huang Z, Zhai K, Ke SQ, Ping YF, Feng H, Rich JN, Yu JS, Bao S*, Bian XW*.  Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy.  Cell Stem Cell.  21: 591-603; 2017.
10. Man J, Yu X, Huang H, Zhou W, Xiang C, Huang H, Miele L, Liu Z, Bebek G, Bao S, Yu JS.  Hypoxic induction of vasorin regulates Notch1 turnover to maintain glioma stem-like cells.  Cell Stem Cell.  22: 104-118; 2018.
11. Wang X, Prager BC, Wu Q, Kim LJY, Gimple RC, Shi Y, Yang K, Morton AR, Zhou W, Zhu Z, Obara EAA, Miller TE, Song A, Lai S, Hubert CG, Jin X, Huang Z, Fang X, Dixit D, Tao W, Zhai K, Chen C, Dong Z, Zhang G, Dombrowski SM, Hamerlik P, Mack SC, Bao S, Rich JN. Reciprocal signaling between glioblastoma stem cells and differentiated tumor cells promotes malignant progression. Cell Stem Cell.  22: 514-528; 2018.
12. Jin X, Kim LJY, Wu Q, Wallace LC, Prager BC, Sanvoranart T, Gimple RC, Wang X, Mack SC, Miller TE, Huang P, Valentim CL, Zhou QC, Barnholtz-Sloan JS, Bao S, Sloan AE, Rich JN.  Targeting glioma stem cells through combined BMI1 and EZH2 inhibition. Nature Medicine. 23:1352-1361; 2017.
13. Shi Y, Ping YF, Zhou W, He ZC, Chen C, Bian BS, Zhang L, Chen L, Lan X, Zhang XC, Zhou K, Liu Q, Long H, Fu TW, Zhang XN, Cao MF, Huang Z, Fang X, Wang X, Feng H, Yao XH, Yu SC, Cui YH, Zhang X, Rich JN, Bao S*, Bian XW*. Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth. Nature Commun. 8:15080; 2017.
14. Fang X, Zhou W, Wu Q, Huang Z, Shi Y, Chen C, Xie Q, Mack SC, Wang X, Carcaboso AM, Sloan AE, Ouyang G, McLendon RE, Bian X-W, Rich JN, Bao S*. Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBX14-mediated Myc ubiquitination. J. Exp. Med. 214:245-267; 2017.
15. Shi Y, Zhou W, Cheng L, Chen C, Huang Z, Fang X, Wu Q, He Z, Xu S, Lathia SD, Ping Y, Rich JN, Bian X-W, Bao S*. Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells. Cell Death Differ. 24:167-180; 2017.
16. Wang X, Yang K, Xie Q, Wu Q, Mack SC, Shi Y, Kim LJY, Prager BC, Flavahan WA, Liu X, Singer M, Hubert CG, Miller TE, Zhou W, Huang Z, Fang X, Regev A, Suvà ML, Hwang TH, Locasale JW, Bao S, Rich JN. Purine synthesis promotes maintenance of brain tumor initiating cells in glioma. Nature Neurosci.  20:661-673; 2017.
17. Xie Q, Wu Q, Kim L, Miller TE, Liau BB, Mack SC, Yang K, Factor DC, Fang X, Huang Z, Zhou W, Alazem K, Wang X, Bernstein BE, Bao S, Rich JN.  RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation. J Clin Invest.  126:2757-2772; 2016.
18. Zhou W, Ke SQ, Huang Z, Flavahan W, Fang X, Paul J, Wu L, Sloan AE, McLendon RE, Li X, Rich JN, Bao S*. Periostin Secreted by Glioblastoma Stem Cells Recruits M2 Tumor-associated Macrophages and Promotes Malignant Growth. Nature Cell Biol. 17:170-182; 2015.
19. Xie Q, Wu Q, Horbinski C, Flavahan WA, Yang K, Zhou W, Dombrowski S, Huang Z, Fang XF, Bao S, Rich JN.Mitochondrial Control by DRP1 in Brain Tumor Initiating Cells.  Nature Neurosci.  18: 501-510; 2015.
20. Fang X, Huang Z, Zhou W, Wu Q, Sloan AE, Ouyang G, McLendon RE, Yu JS, Rich JN, Bao S*. The zinc finger transcription factor ZFX is required for maintaining the tumorigenic potential of Glioblastoma stem cells.  Stem Cells. 32: 2033-2047; 2014.
21. Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, Min W, McLendon RE, Rich JN, and Bao S*.  Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth.  Cell.  153: 139-152; 2013.
22. Cheng L, Wu Q, Zhi Huang, Guryanova OA, Shou W, Rich JN, and Bao S*. L1CAM regulates DNA damage checkpoint response through NBS1. EMBO J. 30: 800-813; 2011.
23. Guryanova OA, Wu Q, Cheng L, Lathia JD, Huang Z, Yang J, MacSwords J, Eyler CE, McLendon RE, Heddleston JM, Shou W, Hambardzumyan D, Lee J, Hjelmeland AB, Sloan AE, Bredel M, Stark GR, Rich JN, and Bao S*. Non-receptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3.  Cancer Cell.  19: 498-511; 2011.
24. Huang Z, Wu Q, Guryanova OA, Cheng L, Shou W, Rich JN, and Bao S*. Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells. Nature Cell Biol. 13: 142-152; 2011.

         (Selected from recent publications)