Shideng Bao, Ph.D.
Director, Center for Cancer Stem Cell Research
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
Glioblastoma (GBM) is the most common and lethal type of primary brain tumor. 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 glioma stem cells (GSCs). Our goal is to develop novel therapeutics targeting GSCs 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 improveGBM 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 goalis 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.
Malignant brain tumors including glioblastomas and brain metastases represent some of the most lethal cancers. Despite maximal therapy, the treatment of malignant brain tumors remains largely ineffective due to therapeutic resistance and the blood-tumor barrier. Thus, development of more effective novel therapeutics is urgently needed. Our mission is to advance the understanding and treatment of malignant brain tumors with the goals of improving and extending the lives of patients affected by these lethal cancers.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Zhou W, Cheng L, Shi Y, Ke SQ, Huang Z, Fang X, Chu CW, Xie Q, Bian XW, Rich JN, Bao S*. Arsenic Trioxide Disrupts Glioblastoma Stem Cells via Promoting PML Degradation to Inhibit Tumor Growth. Oncotarget. 6: 37300-37315; 2015.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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)
Dr. Bao’s team found that treating preclinical models of glioblastoma with verubecestat, a BACE1-inhibiting drug, reduces cancer progression by targeting a class of immune cells abundant in tumors.
Dr. Bao’s group found that inhibiting DNA-PK overturns the pro-cancer properties of glioma stem cells and suppresses tumor growth in preclinical models, suggesting DNA-PK as a potential therapeutic target for treating glioblastoma.
Dr. Bao’s team found that WISP1, a key protein in the Wnt/β-catenin-WISP1 signaling pathway, contributes to glioblastoma progression by maintaining glioma stem cells and tumor-associated macrophages, and that blocking the pathway helped control the disease in preclinical models.