Characterization of Glial Progenitor Cells in Postnatal Human Subcortical White Matter
Preliminary work from our laboratory suggests that postnatal human GPCs, unlike their rodent counterparts, are organized as proliferative clusters along radially oriented columns of microvasculature. We are interested in several important questions:
- What is the cellular composition of the glial progenitor niche in the subcortical white matter?
- Which cell type corresponds to the primary glial progenitors?
- Where are new glia born and which human brain region(s) do they serve?
- How is this system altered in the setting of glioma formation?
Through a combination of immunohistochemical, ultrastructural, and cell culture techniques, we are defining the organization and lineage of subcortical white matter progenitors in the human brain. Altogether, this work will comprehensively characterize the GPC niche in the human brain for the first time.
Delineating the Relationship between Human Gliomas and Endogenous Stem Cell Niches
Despite progress in research on the molecular aspects of malignant gliomas, the prognosis of these brain tumors continues to be dismal. With glioblastomas, the most common high-grade glioma variant in adults, the median length of survival has remained at 12 months for decades. One reason for the lack of clinical advances is ignorance of the cellular origin of this disease.
Recent work identifying a progenitor cell origin of gliomas presents an opportunity to improve our understanding of this disease. Using glioma-specific biomarkers administered to patients before neurosurgical resection, we are exploring the in vivo interface between human GPCs and infiltrative human glioma cells. Based on our emerging understanding of CNS progenitor systems, this work adapts organotypic slice-culture and lineage-tracing techniques to uncover the in vivo response of CNS stem cell niches to human gliomagenesis.
Identifying New Molecular Markers Associated with the Germinal Niche of Human Glial Progenitor Cells
The limited selection of validated GPC-specific markers restricts the potential to define the cellular constituents of the human GPC niche. Expression analysis of microdissected human subcortical white matter is being used, in partnership with Dr. Michael Berens, PhD, of the Translational Genomics Research Institute, to generate a temporospatial map of transcription factor (TF)-encoding genes upregulated in human GPC populations.
By creating a human GPC ‘transcriptome,’ we are identifying programs shared among GPCs and gliomas, and validating new human GPC-specific molecular markers by characterizing their distribution in the pediatric and adult human brain. The resultant TF-encoding gene maps highlight the regulatory and cell-specific machinery activated by developing human GPC populations and provide insight into how these cells may become deregulated and contribute to gliomagenesis.
Identifying Magnetic Resonance Spectral Signatures for Human Progenitor Cell Populations
The size and complexity of the human brain, combined with the ethical boundaries related to human research, compel the need for new approaches capable of identifying human CNS germinal activity in vivo. Preliminary work from our laboratory reveals that ultrahigh-field strength magnetic resonance spectroscopy (MRS) can distinguish CNS progenitor populations through identification of unique metabolic signatures. In conjunction with Jeffrey Yarger, PhD, Director of the Arizona State University Magnetic Resonance Research Center, a combined in vitro and in vivo approach to MRS analysis of human GPCs is being developed to identify and validate the spectral signature(s) of progenitor populations in live human brain tissue.
Signatures corresponding to normal human GPCs may also identify cancerous progenitor cells in human glioma patients, because these two populations share many of the same metabolic pathways. The ability to localize and track human CNS progenitor populations in vivo and in real-time will not only enhance our understanding of human germinal region development but elucidate its response to disease.
Characterizing the Role of Cell Polarity in Glioma Cell Invasion and Drug Resistance
Although gain-in-function in epidermal growth factor receptor (EGFR) signaling is commonly associated with high-grade gliomas at presentation, targeted therapy with EGFR kinase inhibitors has failed to achieve adequate clinical success. Recent work done in conjunction with Sourav Gosh, PhD, at the University of Arizona, has shown that glioma co-culture with differentiated macrophages renders EGFR kinase inhibitor ineffective. Macrophages play an important role in tumor-associated inflammation and drive oncogenic signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-Kappa-B) in cancer cells.
Interestingly, oncogenic mutations driving NF-Kappa-B activation are rare in cancer. It is believed that NF-Kappa-B activation in tumors is a result of the inflammatory microenvironment. The mechanism of glioma-specific NF-Kappa-B activation and NF-Kappa-B function remain largely undefined. Importantly, atypical protein kinase C (aKPC) is a fundamental component of both EGFR and NF-Kappa-B signaling pathways in GBM cells. Using a combination of molecular and cell biology techniques, we are examining the impact of glioma-associated macrophages in promoting glioma invasion and contributing to EGFR kinase inhibitor resistance through NF-Kappa-B and aPKC-dependent signaling.
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