Director, Center for Cancer Stem Cell Research
Location: Cleveland Clinic Main Campus
Glioblastoma (GBM) is the most common and lethal type of primary brain tumor highly resistant to current therapy. 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 cellular and molecular interactions between GSCs and other cells including tumor-associated macrophages in the tumor microenvironment (TME). Our goal is to develop novel therapeutics targeting GSCs and the interplay between GSCs and the TME to improve GBM treatment.
Shideng Bao, Ph.D. is a Full Staff in the Department of Cancer Biology, and the Director of Center for Cancer Stem Cell Research at Cleveland Clinic Lerner Research Institute. Before he joined Cleveland Clinic, he was an Associate Professor in Departments of Radiation Oncology and Neurosurgery at University of Colorado Denver. He did postdoctoral trainings at Baylor College of Medicine and Duke University Medical Center. He became an Assistant Professor in 2005 at Duke Brain Tumor Center where he started his research program on glioma stem cells (GSCs) and demonstrated that GSCs contribute to radioresistance of GBM (Nature, 2006). Since then, his team made several important contributions in understanding the molecular regulation of cellular hierarchy and plasticity of GSCs as well as therapeutic targeting of GSCs resulting in high-profile papers in Cell, Cancer Cell, Cell Stem Cell, Nature Cell Biology, JEM, Science Translational Medicine, Nature Cancer, and Nature Communications. His lab discovered that: (1) BMX-mediated STAT3 activation is required for maintaining the self-renewal and tumorigenic potential of GSCs (Cancer Cell, 2011); (2) GSCs generate the majority of vascular pericytes to support tumor vasculature and malignant growth in GBM (Cell, 2013); (3) Targeting GSC-derived pericytes disrupts the blood-tumor barrier (BTB) and enhances drug delivery into GBM to improve chemotherapeutic efficacy (Cell Stem Cell, 2017); (4) GSCs and tumor-associated macrophages (TAMs) interplay through several bi-directional signaling to support malignant growth in GBM (Nat. Cell Biol., 2015; Nat. Commun., 2017; 2020); (5) Targeting GSCs through BMX inhibition by Ibrutinib potently suppresses tumor growth and synergizes with radiation to improve therapeutic efficacy for GBM (Sci. Trans. Med. 10:eahh6818, 2018), which led to an ongoing clinical trial using Ibrutinib plus radiation for GBM treatment (NCT03535350); and (6) BACE1 inhibition reprograms tumor-associated macrophages (TAM) and potently inhibits GBM tumor growth (Nature Cancer, 2021). The goal of his research is to develop novel therapeutics targeting GSCs, the BTB, and tumor-promoting TAMs (pTAMs) to effectively improve GBM treatment and the patient survival.
Molecular Cell Biology
Undergraduate - Wuhan University
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 from recent publications)
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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.