Our lab broadly studies cancer stem cell biology, cellular signaling, and therapy responses in human brain tumors, in particular, glioblastoma (GBM). We have a range of different projects currently underway in glioma cell lines, cancer stem cells, and mice models.
Integrated genomic analysis by The Cancer Genome Atlas (TCGA) revealed that GBMs can be classified into four clinically relevant subtypes: proneural (PN), neural, mesenchymal (Mes), and classical GBMs. Each subtype is characterized by distinct gene expression signatures and genetic alterations. We reported that PN and Mes glioma stem cells (GSCs) subtypes also have distinct dysregulated signaling pathways. Our current research focuses on novel mechanisms/cellular signaling of GSC biology, tumorigenesis, progression, invasion/metastasis, angiogenesis, and therapy responses of GSCs and GBMs.
MicroRNAs (miRs) and non-coding RNAs in GSCs and GBMs
miRs and other small non-coding RNAs act as transcription repressors or inducers of gene expression or functional modulators in all multicellular organisms. Dysregulated miRs/noncoding RNAs plays critical roles in cancer initiation, progression and responses to therapy. We study the mechanisms by which deregulated expression of miRs influence GBM malignant phenotypes through interaction with signaling pathways, that in turn, influence proneural (PN)- and mesenchymal (Mes)-associated gene expression in GSCs and GBM phenotypes. We study the molecular consequences and explore clinical applications of modulating miRs and signaling pathways in GBMs. We are establishing profiles of non-coding RNAs in these GSCs and study mechanisms and biological influences of these non-coding RNAs in regulating GSC biology and GBM phenotypes. In addition, we explore novel therapeutic approaches of delivery of tumor suppressive miRs into GSC brain xenografts in animals.
Autophagy in GBMs
(Macro)autophagy is an evolutionally conserved dynamic process whereby cells catabolize damaged proteins and organelles in a lysosome-dependent manner. Autophagy principally serves as an adaptive role to protect cells and tissues, including those associated with cancer. Autophagy in response to multiple stresses including therapeutic treatments such as radiation and chemotherapies provides a mechanism for tumor cell to survive and acquire resistance to therapies. Tumors can use autophagy to support and sustain their proliferation, survival, metabolism, invasiveness, metastasis, and resistance to therapy. We study mechanisms by which phosphorylation, acetylation and ubiquitination of autophagy proteins regulate GSC and GBM phenotypes and autophagic response, which, in turn contributes to tumor cell survival, growth and resistance to therapy. We investigate whether disruption of these post-translational processes on autophagy proteins inhibits autophagy and enhances the efficacy of combination therapies for GBMs. We examine whether cross-talks between miRs, autophagy, and oncogenic signaling pathways regulate GSC stemness and phenotypes.
Heterogeneity, epigenetic regulation, DNA damage and metabolic pathways in GSCs and GBMs
Intratumoral heterogeneity is a characteristic of GBMs and most of cancers. Phenotypic and functional heterogeneity arise among GBM cells within the same tumor as a consequence of genetic change, environmental differences and reversible changes in cell properties. Subtype mosaicism within the same tumor and spontaneous conversion of human PN to Mes tumors have been observed in clinical GBMs. We explore an emerging epigenetic marker with distinct functions such as DNA methylation together with genetic mapping of these markers to assess their contributions to GBM heterogeneity. In addition, compared with PN GSCs, DNA damage and glycolytic pathways are aberrant active in Mes GSCs. We investigate the mechanisms by which these pathways regulate GSC and GBM phenotypes and responses to therapies.
Oncogenic receptor tyrosine kinase (RTKs) signaling, small Rho GTPase regulators in GBM and GSCs
Small Rho GTPases such as Rac1 and Cdc42 modulate cancer cell migration, invasion, growth and survival. Recently, we described mechanisms by which EGFR and its mutant EGFRvIII, and PDGFR alpha promote glioma growth and invasion by distinct mechanisms involving phosphorylation of Dock180, a Rac-specific guanidine nucleotide exchange factor (GEF) and DCBLD2, an orphan membrane receptor. We are currently investigating involvement of other modulators/GEFs and other Rho GTPases in modulating GSC and GBM phenotypes and responses to therapy.
We welcome your questions and comments. For general feedback and inquries, please contact us.
Contact Shi-Yuan Cheng, PhD, about the following available lab positions.
- Postdoctoral Fellows
- Rotating Graduate Students
Administrative Phone: 312-503-3043
Lab Phone: 312-503-5314