Browsing by Author "Wu, Q"

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c-Myc is required for maintenance of glioma cancer stem cells.
(PLoS One, 2008) Wang, J; Wang, H; Li, Z; Wu, Q; Lathia, JD; McLendon, RE; Hjelmeland, AB; Rich, JN
BACKGROUND: Malignant gliomas rank among the most lethal cancers. Gliomas display a striking cellular heterogeneity with a hierarchy of differentiation states. Recent studies support the existence of cancer stem cells in gliomas that are functionally defined by their capacity for extensive self-renewal and formation of secondary tumors that phenocopy the original tumors. As the c-Myc oncoprotein has recognized roles in normal stem cell biology, we hypothesized that c-Myc may contribute to cancer stem cell biology as these cells share characteristics with normal stem cells. METHODOLOGY/PRINCIPAL FINDINGS: Based on previous methods that we and others have employed, tumor cell populations were enriched or depleted for cancer stem cells using the stem cell marker CD133 (Prominin-1). We characterized c-Myc expression in matched tumor cell populations using real time PCR, immunoblotting, immunofluorescence and flow cytometry. Here we report that c-Myc is highly expressed in glioma cancer stem cells relative to non-stem glioma cells. To interrogate the significance of c-Myc expression in glioma cancer stem cells, we targeted its expression using lentivirally transduced short hairpin RNA (shRNA). Knockdown of c-Myc in glioma cancer stem cells reduced proliferation with concomitant cell cycle arrest in the G(0)/G(1) phase and increased apoptosis. Non-stem glioma cells displayed limited dependence on c-Myc expression for survival and proliferation. Further, glioma cancer stem cells with decreased c-Myc levels failed to form neurospheres in vitro or tumors when xenotransplanted into the brains of immunocompromised mice. CONCLUSIONS/SIGNIFICANCE: These findings support a central role of c-Myc in regulating proliferation and survival of glioma cancer stem cells. Targeting core stem cell pathways may offer improved therapeutic approaches for advanced cancers.
Open Access
Learning gradients on manifolds
(BERNOULLI, 2010-02) Mukherjee, S; Wu, Q; Zhou, DX
Open Access
Learning gradients: Predictive models that infer geometry and statistical dependence
(Journal of Machine Learning Research, 2010-08-01) Wu, Q; Guinney, J; Maggioni, M; Mukherjee, S
The problems of dimension reduction and inference of statistical dependence are addressed by the modeling framework of learning gradients. The models we propose hold for Euclidean spaces as well as the manifold setting. The central quantity in this approach is an estimate of the gradient of the regression or classification function. Two quadratic forms are constructed from gradient estimates: the gradient outer product and gradient based diffusion maps. The first quantity can be used for supervised dimension reduction on manifolds as well as inference of a graphical model encoding dependencies that are predictive of a response variable. The second quantity can be used for nonlinear projections that incorporate both the geometric structure of the manifold as well as variation of the response variable on the manifold. We relate the gradient outer product to standard statistical quantities such as covariances and provide a simple and precise comparison of a variety of supervised dimensionality reduction methods. We provide rates of convergence for both inference of informative directions as well as inference of a graphical model of variable dependencies. © 2010.
Open Access
Microgels formed by enzyme-mediated polymerization in reverse micelles with tunable activity and high stability
(RSC Advances, 2015-01-01) Bao, S; Wu, D; Su, T; Wu, Q; Wang, Q
This communication describes the preparation of microgels via enzyme-triggered inverse emulsion polymerization, which provides an effective method for immobilizing enzymes with tunable catalytic performance and high stability.
Open Access
Prostate Bed Motion During Post-Prostatectomy Radiotherapy
(MEDICAL PHYSICS, 2012-06) Xu, Z; Li, T; Lee, W; Hood, R; Godfrey, D; Wu, Q
Open Access
Targeting A20 decreases glioma stem cell survival and tumor growth.
(PLoS Biol, 2010-02-23) Hjelmeland, AB; Wu, Q; Wickman, S; Eyler, C; Heddleston, J; Shi, Q; Lathia, JD; Macswords, J; Lee, J; McLendon, RE; Rich, JN
Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs). GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets. We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kappaB pathway, is overexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels. To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFalpha-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GSCs to TNFalpha-mediated apoptosis. The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these cells to self-renew in primary and secondary neurosphere formation assays. The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human glioma xenografts. In silico analysis of a glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival. Together these data indicate that A20 contributes to glioma maintenance through effects on the glioma stem cell subpopulation. Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in glioma through promotion of GSC survival. A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type.