Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data from human glioma cancer stem cell (CSC) specimens following knockdown of GREM1

ABSTRACT: CSCs differentially secrete the BMP antagonist Gremlin1 compared to non-stem glioma populations. Knockdown of Gremlin1 decreases CSC proliferation and tumorigenicity, establishing Gremlin1 as an essential effector for CSC maintenance. We used a microarray to determine the gene expression programs that are activated downstream of Gremlin1 that might be responsible for CSC maintenance. Glioma CSC cultures from two distinct patient-derived specimens (528 and 3691) were transduced with lentivirus expressing non-targeting scrambled shRNA or one of two distinct Gremlin1 shRNAs (shGrem1_485 and shGrem1_2456) for 72 hours (total of six samples). RNA was extracted for array hybridization.

ORGANISM(S): Homo sapiens

SUBMITTER: Kenneth Yan

PROVIDER: E-GEOD-52846 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy.

Yan Kenneth K Wu Qiulian Q Yan Diana H DH Lee Christine H CH Rahim Nasiha N Tritschler Isabel I DeVecchio Jennifer J Kalady Matthew F MF Hjelmeland Anita B AB Rich Jeremy N JN

Genes & development 20140501 10

Glioblastomas are the most prevalent and lethal primary brain tumor and are comprised of hierarchies with self-renewing cancer stem cells (CSCs) at the apex. Like neural stem cells (NSCs), CSCs reside in functional niches that provide essential cues to maintain the cellular hierarchy. Bone morphogenetic proteins (BMPs) instruct NSCs to adopt an astrocyte fate and are proposed as anti-CSC therapies to induce differentiation, but, paradoxically, tumors express high levels of BMPs. Here we demonstr ...[more]

PMID: 24788093

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Project description:In this study, we explored the transcriptomic consequences of strong activation of the Notch pathway in embryonic human neural stem cells and in gliomas. For this we used a forced expression of the Notch intracellular domain (NICD). Glioblastoma multiforms (GBMs) are highly vascularized brain tumors containing a subpopulation of multipotent cancer stem cells. These cells closely interact with endothelial cells in neurovascular niches. In this study we have uncovered a close link between the Notch1 pathway and the tumoral vascularization process of GBM stem cells. We observed that although the Notch1 receptor was activated, the typical target proteins (HES5, HEY1, HEY2) were not or barely expressed in two explored GBM stem cell cultures. Notch1 signalling activation by expression of the intracellular form (NICD) in these cells was found to reduce their growth rate and migration which was accompanied by the sharp reduction of neural stem cell transcription factor expression (ASCL1, OLIG2, SOX2) while HEY1/2, KLF9, SNAI2 transcription factors were upregulated. Expression of OLIG2 and growth were restored after termination of Notch1 stimulation. Remarkably, NICD expression induced the expression of pericyte cell markers (NG2, PDGFRb and a-smooth muscle actin (aSMA)) in GBM stem cells. This was paralleled with the induction of several angiogenesis-related factors most notably cytokines (HB-EGF, IL8, PLGF), metalloprotease (MMP9) and adhesion proteins (VCAM-1, ICAM-1, ITGA9). In xenotransplantation experiments, contrasting with the infiltrative and poorly-vascularized tumors obtained with control GBM stem cells, Notch1 stimulation resulted in poorly-disseminating but highly-vascularized grafts containing large vessels with lumen. Notch1-stimulated GBM cells expressed pericyte cell markers and closely associated with endothelial cells. These results reveal an important role for the Notch1 pathway in regulating GBM stem cell plasticity and angiogenic properties. Embryonic human neural progenitors obtained from Lonza, the U87 glioma cell line, and glioma cancer stem cells (Gb4 and Gb7) characterized in Guichet et al. (Glia, 2013, 61(2), 225-39) were infected with lentiviruses expressing YFP or YFP-IRES-NICD (activated form of Notch receptor). After 48h, RNA were extracted for Affymetrix microarray analysis.

Dataset Information

Expression data from human glioma cancer stem cell (CSC) specimens following knockdown of GREM1

Publications

Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy.

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