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| Status |
Public on Jun 04, 2014 |
| Title |
Effect of Notch1 pathway activation on high-grade glioma cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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.
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| Contributor(s) |
Hugnot JP, Guichet PO, Rothhut B |
| Citation(s) |
24898819 |
| Submission date |
Feb 21, 2013 |
| Last update date |
Nov 08, 2016 |
| Contact name |
jean-philippe hugnot |
| E-mail(s) |
jean-philippe.hugnot@umontpellier.fr
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| Organization name |
inserm inm u1191
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| Lab |
brain plasticity, stem cell and glial tumors
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| Street address |
IGF INSERM UM 141 rue de la cardonille
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| City |
MOntpellier |
| State/province |
languedoc |
| ZIP/Postal code |
34094 |
| Country |
France |
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| Platforms (1) |
| GPL11532 |
[HuGene-1_1-st] Affymetrix Human Gene 1.1 ST Array [transcript (gene) version] |
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| Samples (8)
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| GSM1086967 |
Human neural stem cell infected with YFP lentivirus |
| GSM1086968 |
Human neural stem cell infected with YFP-NICD lentivirus |
| GSM1086969 |
U87 cell line infected with YFP lentivirus |
| GSM1086970 |
U87 cell line infected with YFP-NICD lentivirus |
| GSM1086971 |
Gb4 glioma stem cells infected with YFP lentivirus |
| GSM1086972 |
Gb4 glioma stem cells infected with YFP-NICD lentivirus |
| GSM1086973 |
Gb7 glioma stem cells infected with YFP lentivirus |
| GSM1086974 |
Gb7 glioma stem cells infected with YFP-NICD lentivirus |
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| Relations |
| BioProject |
PRJNA190058 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE44561_RAW.tar |
36.8 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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