Neuro-Oncology Research

Research Description

Our lab broadly studies cancer stem cell biology, cellular signaling, RNA biology, and therapy responses in human brain tumors, in particular, glioblastoma (GBM). We have a range of different projects currently underway in glioma cell lines, gliomas stem-like cells (GSCs), patient-derived xenograft (PDX) GBM model, human iPSC-derived glioma organoid model, orthotopic glioma xenograft model in mice, and clinical glioma tumor specimens. Our current research focuses on novel mechanisms/cellular signaling of GSC biology, tumorigenesis, progression, and therapy responses of GSCs and GBMs.

Roles of RNA alternative splicing and RNA-binding proteins in glioma

RNA alternative splicing (AS), an evolutionarily conserved co-transcriptional process, is an important and influential determinant of transcriptome and proteome landscapes in normal and disease states such as cancer. AS is regulated by a group of RNA binding proteins (RBPs) that bind to the cis-acting elements in proximity to a splice site thus affecting spliceosome assembly. In cancers, altered expression of or mutations in RBPs result in dysregulated AS that impacts cancer biologic properties. We have established AS/RBP networks that are dysregulated in both adult and pediatric gliomas through bioinformatic analysis of both public and our own datasets of clinical glioma tumors. We are investigating the biological significance of AS/RBPs dysregulation in glioma progression and therapy response by using human iPSC-derived glioma organoid model and GSC brain xenograft models in animals. In addition, we are exploring novel therapeutic approaches of targeting glioma-associated AS/RBP networks to treat GBMs.

Roles of Non-coding RNAs in glioma 

Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), act as transcription repressors or inducers of gene expression or functional modulators in all multicellular organisms.  Dysregulated ncRNAs plays critical roles in cancer initiation, progression and responses to therapy. We study the mechanisms by which deregulated expression of lncRNAs or circRNAs influence GBM malignant phenotypes through interactions with signaling pathways. We study the molecular consequences and explore clinical applications of modulating ncRNAs and related oncogenic signaling pathways in GBM.  We are establishing profiles of ncRNAs in clinical gliomas and patient-derived GSCs, and study mechanisms and biological influences of these ncRNAs in regulating GSC biology and GBM phenotypes. 

Aberrant DNA and RNA structures in therapy-resistant GBM

Standard of care treatment for GBM includes the DNA damaging agent temozolomide (TMZ), which has a known mechanism of action to target and mutate guanine bases. With this knowledge in hand, we sought to determine the effects of guanine (G) mutations in DNA and RNA secondary structure. G’s are important for creating structures like g-quadruplexes in both DNA and RNA which can affect changes in translation or be used as docking sites for DNA repair and RNA binding proteins. Using whole genome sequencing data along with isogenic drug sensitive and resistant lines, we are investigating the role of G mutations in DNA and RNA secondary structure to determine potential therapeutic avenues with the help of a chemical biologist to create novel drugs to target these TMZ-induced aberrant pathways.

Targeting autophagy to treat glioma

Autophagy is an evolutionarily conserved process that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism, thus serving as a protective mechanism against stressors and diverse pathologies including cancer. We study mechanisms by which phosphorylation, acetylation and ubiquitination of autophagy-related 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 in autophagy-related proteins inhibits autophagy and enhances the efficacy of combination therapies in GBMs. In collaboration with a medicinal chemist, we are characterizing a next generation of novel autophagy inhibitors that specifically target a key autophagy regulator that we recently reported.

Multi-omics and GBM non-responsiveness to immunotherapies

GBM is categorized as a “cold” tumor that does not respond to current immunotherapies using various immune-checkpoint blockers. Although extensive efforts have been made to sensitize GBM to immunotherapies, the mechanistic studies to determine alternative therapies from understanding the underlying signaling and clinical trial results are still disappointing. We are interested in utilizing the information of multi-omics of clinical gliomas, in particular, proteomics profiling in relation to genomic and epigenomic profiling, to identify potential protein targets that could be the major modulators through post-translational modifications in these “cold” GBM tumors. We will also consider the involvement of tumor microenvironment and immune cells in these conditions. These studies are a brand-new direction that are high-risk and high-reward to turn “cold” GBM tumors to immunotherapy responsive tumors.

For more information, please see Dr. Cheng's faculty profile and lab website.

Publications

View Dr. Cheng's complete list of publications in PubMed.

Contact Us

Shi-Yuan Cheng, PhD at 312-503-5314

Visit us on campus in the Lurie Building, Room 6-119, 303 E Superior Street, Chicago, Illinois 60611.

Research Description

Our research program is aimed at understanding the genetic program that underlies the pathogenesis of Glioblastoma multiforme (GBM), the most prevalent and malignant form of brain cancer. Applying a combination of cell/molecular biology, oncogenomic and mouse engineering approaches, we are dedicated to systematically characterize novel gliomagenic oncogenes and tumor suppressors. We will functionally delineate and validate these pathways using cell culture and animal models and develop novel nanotechnological approaches to target these aberrations in established tumors.

For more information see the faculty profile of Alexander H. Stegh MD, PhD.

Recent Publications

View Dr. Stegh's full list of publications at PubMed.

Contact

Email Alexander Stegh, MD, PhD 

Phone: 312-503-2879

Twitter: @ahstegh

Research Description

RNA Processing and Neurodegeneration: Accumulating evidence supports that aberrant RNA processing represents a general pathogenic mechanism for neurodegeneration, including dementia and amyotrophic lateral sclerosis (ALS). A number of RNA binding proteins (RBPs) have been associated with neurodegenerative diseases, especially various proteinopathies. Recent studies have defined TDP-43 and FUS proteinopathies, a group of heterogeneous neurodegenerative disorders overlapping with dementia, including frontotemporal lobar degeneration (FTLD) and ALS. Several important questions drive our research: what is physiological function of these RBPs? What are the fundamental mechanisms by which genetic mutations in or aberrant regulation of these RBPs cause neural damage? What are the earliest detectable molecular and cellular events that reflect the neural damage in these devastating neurological diseases? How to reverse/repair the neural damage and slow down the progression of these devastating diseases.

To address these questions, we have established cellular and animal models for both TDP-43 and FUS proteinopathies (Li et al, 2010;Barmada et al, 2010; Chen et al, 2011; Fushimi et al, 2011). Using combined biochemical, biophysical, molecular biology and cell biology approaches, we have begun to examine the molecular pathogenic mechanisms underlying neurotoxicity induced by TDP-43 and FUS. Our recent work using atomic force microscopy (AFM), electron microscopy (EM) and (NMR) approaches has shown the biochemical, biophysical and structural similarities between TDP-43 and classical amyloid proteins (Guo et al, 2011; Xu et al, 2013; Bigio et al, 2013). Our study has defined a minimal amyloidogenic region at the carboxyl terminal domain of TDP-43 that is sufficient for amyloid fibril formation and neurotoxicity (Guo et al, 2011; Zhu et al, unpublished). Using cellular and animal models for FUS proteinopathy, we have begun to identify the earliest detectable cellular damage caused by mutations in and overexpression of the human FUS gene. Our data have provided new insights into pathogenic mechanisms underlying these proteinopathies and suggested candidate targets for developing therapeutic approaches.

A critical step in mammalian gene expression is the removal of introns by the process of pre-mRNA splicing. Alternative pre-mRNA splicing, the process of generating multiple mRNA transcripts from a single genetic locus by alternative selection of distinct splice sites, is one of most powerful mechanisms for genetic diversity and an excellent means for fine-tuning gene activity. Many genes critical for neuronal survival and function undergo extensive alternative splicing. Splicing defects play important roles in neurodegenerative disorders such as dementia and motor neuron diseases. For example, splicing mutations in the human tau gene and imbalance of tau splicing isoforms lead to frontotemporal lobar degeneration with tau-positive pathology (FTLD-tau). To understand mechanisms underlying FTLD-tau, we have set up a model system and developed a number of biochemical, molecular and cell biological assays to study alternative splicing of the human tau gene. Our work has led to the identification of a number of cis-elements and trans-acting RBPs controlling tau alternative splicing (Kar et al, 2006; Wu et al, 2006; Kar et al, 2011; Ray et al, 2011). Our experiments have begun to reveal previously unknown players in FTLD-tau and provided new candidate target genes for developing therapeutic strategy (Donahue et al, 2006; unpublished).

Molecular Mechanisms Regulating Axon Guidance, Cell Migration & Tumor Metastasis: Another line of our research focuses on the cellular and molecular mechanisms regulating cell migration and cancer metastasis. Previous studies from our group and others led to the discovery of Slit as a prototype of neuronal guidance cue. Our studies have shown that Slit interacts with Roundabout (Robo) and acts as a chemorepellent for axons and migrating neurons (Wu et al, 1999; Li et al, 1999;Yuasa-Kawada et al, 2009). Our work has demonstrated that Slit-Robo signaling modulates chemokines and inhibits migration of different types of cells, including cancer cells. The observation that Slit is frequently inactivated in a range of tumors suggests an important role of Slit in tumor suppression. We have established several assays and shown that Slit inhibits invasion and migration of cancer cells, including breast cancer, glioma and prostate cancer. We are using combined molecular and cell biology approaches to dissecting Slit-Robo signaling in neuronal guidance and tumor suppression. Our research has provided new insights into signal transduction pathways mediating Slit function. Enhancing or activating the endogenous mechanisms that restrict or suppress cancer invasion/metastasis will likely provide novel approaches to cancer metastasis. 

For more information please view the faculty profile of Jane Wu, MD, PhD or visit the Wu Lab website.

Publications

View a full list of publications by Jane Wu at PubMed.

Contact

Email Jane Wu, MD, PhD 

Phone: 312-503-0684