Publications (8)43.93 Total impact
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Article: Yin and yang: cancer-implicated miRNAs that have it both ways.
Cell cycle (Georgetown, Tex.) 11/2009; 8(22):3611-2. · 5.36 Impact Factor -
Article: The ABCG2 resistance network of glioblastoma.
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ABSTRACT: Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor variant. It exhibits heterogeneity at both the morphologic and genetic levels, with a complex combination of somatic alterations rendering the tumor class difficult to adequately treat. The role of so-called "cancer stem-cells" (CSCs) in the resistance of high-grade gliomas like GBM to conventional treatment regimens has received much recent attention, especially with regard to the enhanced ability of stem-like cells to activate survival pathways, repair DNA damage, and expel cytotoxic drugs. Furthermore, the biology of GBM is actually even more convoluted, characterized by a constantly changing microenvironment that greatly influences tumor growth and response to therapy. Herein we review the most recently reported genetic events in human glioma patients and their influence on treatment response, particularly in relation to O6-methylguanine-DNA methyltransferase methylation status. We aim to present evidence for a role for cancer stem-like cells and their unique microenvironment in therapy resistance and forward our views on glioma initiation and origin. Finally, given the recent interest in "side population" (SP) cells as a model of CSCs in gliomagenesis, we further describe the function of ABCG2 transporters, the mediators of the SP phenotype, at both the blood-brain barrier and in stem-like tumor cells.Cell cycle (Georgetown, Tex.) 10/2009; 8(18):2936-44. · 5.36 Impact Factor -
Article: Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells.
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ABSTRACT: Recent evidence supports the notion that transformation of undifferentiated neural stem cell (NSC) precursors may contribute to the development of glioblastoma multiforme (GBM). The over-expression and mutation of the epidermal growth factor receptor (EGFR), along with other cellular pathway mutations, plays a significant role in GBM maintenance progression. Though EGFR signaling is important in determining neural cell fate and conferring astrocyte differentiation, there is a limited understanding of its role in NSC and tumor stem cell (TSC) biology. We hypothesized that EGFR expression and mutation in post-natal NSCs may contribute to cellular aggressiveness including enhanced cellular proliferation, survival and migration. Stable subclones of C17.2 murine NSCs were transfected to over-express either the wild-type EGFR (wtEGFR) or its most common mutated variant EGFRvIII. Activated EGFR signaling in these cells induced behaviors characteristic of GBM TSCs, including enhanced proliferation, survival and migration, even in the absence of EGF ligand. wtEGFR activation was also found to block neuronal differentiation and was associated with a dramatic increase in chemotaxis in the presence of EGF. EGFRvIII expression lead to an increase in NSC proliferation and survival, while it simultaneously blocked neuronal differentiation and promoted glial fate. Our findings suggest that activated EGFR signaling enhances the aggressiveness of NSCs. Understanding the regulatory mechanisms of NSCs may lend insight into deregulated mechanisms of GBM TSC invasion, proliferation, survival and resistance to current treatment modalities.Journal of Neuro-Oncology 10/2009; 97(3):323-37. · 3.21 Impact Factor -
Article: Live cell labeling of glial progenitor cells using targeted quantum dots.
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ABSTRACT: This study describes the development of targeted quantum dots (T-QDs) as biomarkers for the labeling of glial progenitor cells (GPCs) that over express platelet derived growth factor (PDGF) and its receptor PDGFR (GPC(PDGF)). PDGFR plays a critical role in glioma development and growth, and is also known to affect multiple biological processes such as cell migration and embryonic development. T-QDs were developed using streptavidin-conjugated quantum dots (S-QDs) with biotinylated antibodies and utilized to label the intracellular and extracellular domains of live, cultured GPC(PDGF) cells via lipofection with cationic liposomes. Confocal studies illustrate successful intracellular and extracellular targeted labeling within live cells that does not appear to impact upstream PDGFR dynamics during real-time signaling events. Further, T-QDs were nontoxic to GPC(PDGF) cells, and did not alter cell viability or proliferation over the course of 6 days. These results raise new applications for T-QDs as ultra sensitive agents for imaging and tracking of protein populations within live cells, which that will enable future mechanistic study of oncogenic signaling events in real-time.Annals of biomedical engineering 06/2009; 37(10):1967-73. · 2.41 Impact Factor -
Article: Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations.
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ABSTRACT: Glioblastoma multiforme (GBM) is an umbrella designation that includes a heterogeneous group of primary brain tumors. Several classification strategies of GBM have been reported, some by clinical course and others by resemblance to cell types either in the adult or during development. From a practical and therapeutic standpoint, classifying GBMs by signal transduction pathway activation and by mutation in pathway member genes may be particularly valuable for the development of targeted therapies. We performed targeted proteomic analysis of 27 surgical glioma samples to identify patterns of coordinate activation among glioma-relevant signal transduction pathways, then compared these results with integrated analysis of genomic and expression data of 243 GBM samples from The Cancer Genome Atlas (TCGA). In the pattern of signaling, three subclasses of GBM emerge which appear to be associated with predominance of EGFR activation, PDGFR activation, or loss of the RAS regulator NF1. The EGFR signaling class has prominent Notch pathway activation measured by elevated expression of Notch ligands, cleaved Notch receptor, and downstream target Hes1. The PDGF class showed high levels of PDGFB ligand and phosphorylation of PDGFRbeta and NFKB. NF1-loss was associated with lower overall MAPK and PI3K activation and relative overexpression of the mesenchymal marker YKL40. These three signaling classes appear to correspond with distinct transcriptomal subclasses of primary GBM samples from TCGA for which copy number aberration and mutation of EGFR, PDGFRA, and NF1 are signature events. Proteomic analysis of GBM samples revealed three patterns of expression and activation of proteins in glioma-relevant signaling pathways. These three classes are comprised of roughly equal numbers showing either EGFR activation associated with amplification and mutation of the receptor, PDGF-pathway activation that is primarily ligand-driven, or loss of NF1 expression. The associated signaling activities correlating with these sentinel alterations provide insight into glioma biology and therapeutic strategies.PLoS ONE 01/2009; 4(11):e7752. · 4.09 Impact Factor -
Article: Glioma formation, cancer stem cells, and akt signaling.
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ABSTRACT: Several recent reports have provided evidence that cancer is initiated by a rare fraction of cells called "cancer stem cells" which are multipotent, self-renewing subset of the tumor. However, several issues regarding the biology and techniques of isolating these cells from solid tumors remain to be clarified. In addition, experimental data supports two possibilities for glioma cell of origin. First, that stem cells or early progenitors are transformed and show variable differentiation of their progeny during tumor development. Second, that more differentiated glia are transformed by genetic events that lead to a loss of differentiation maintenance. In human gliomas, these two theories are not mutually exclusive. In this review we will summarize both theories, and highlight outstanding issues that remain to be resolved.Stem cell reviews 08/2008; 4(3):203-10. · 5.08 Impact Factor -
Article: Somatic cell type specific gene transfer reveals a tumor-promoting function for p21(Waf1/Cip1).
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ABSTRACT: How proteins participate in tumorigenesis can be obscured by their multifunctional nature. For example, depending on the cellular context, the cdk inhibitors can affect cell proliferation, cell motility, apoptosis, receptor tyrosine kinase signaling, and transcription. Thus, to determine how a protein contributes to tumorigenesis, we need to evaluate which functions are required in the developing tumor. Here we demonstrate that the RCAS/TvA system, originally developed to introduce oncogenes into somatic cells of mice, can be adapted to allow us to define the contribution that different functional domains make to tumor development. Studying the development of growth-factor-induced oligodendroglioma, we identified a critical role for the Cy elements in p21, and we showed that cyclin D1T286A, which accumulates in the nucleus of p21-deficient cells and binds to cdk4, could bypass the requirement for p21 during tumor development. These genetic results suggest that p21 acts through the cyclin D1-cdk4 complex to support tumor growth, and establish the utility of using a somatic cell modeling system for defining the contribution proteins make to tumor development.The EMBO Journal 12/2007; 26(22):4683-93. · 9.20 Impact Factor -
Article: Somatic cell type specific gene transfer reveals a tumor-promoting function for p21Waf1/Cip1
The EMBO Journal 01/2007; 26(22):4683-4693. · 9.20 Impact Factor
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Institutions
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2008–2009
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Memorial Sloan-Kettering Cancer Center
- Division of Cancer Biology & Genetics
New York City, NY, USA
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