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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Aug 28, 2009 |
| Title |
Serial transcriptome analysis and cross species integration identifies CENPE as novel neuroblastoma target |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Cancer genomic studies that rely on analysis of diagnostic biopsies from primary tumors may not fully identify the molecular events associated with tumor progression. We hypothesized that characterizing the transcriptome during tumor progression in the TH-MYCN transgenic neuroblastoma model would identify oncogenic drivers that would be targetable therapeutically. We quantified expression of 32,381 murine genes in 9 hyperplastic ganglia harvested at 3 time points, and 4 tumor cohorts of progressively larger size (n=6 each group) in mice homozygous for the TH-MYCN transgene. We found 93 genes that showed a linearly increasing or decreasing pattern of expression from the preneoplastic ganglia to end stage tumors. Cross-species integration identified 24 genes that were highly expressed in human MYCN amplified neuroblastomas. The genes prioritized were not exclusively driven by increasing Myc transactivation or proliferative rate. We manually curated the 24 candidates and prioritized 3 targets (Cenpe, Gpr49, Impdh2) with previously determined roles in cancer. Using siRNA knockdown in human neuroblastoma cell line models we further prioritized CENPE due to potent inhibition of cellular proliferation. Targeting of CENPE with the selective small molecular inhibitor GSK923295 showed potent inhibition of in vitro proliferation of 19 neuroblastoma derived cell lines (median IC50=41 nM; range 27-266 nM), and significantly delayed tumor growth kinetics in 3 xenograft models (p-values ranged from p<0.0001 to p=0.018). Here we provide preclinical validation that serial transcriptome analysis of a transgenic mouse model followed by cross-species integration is a useful method to identify therapeutic targets, and identify CENPE as a novel therapeutic candidate in neuroblastoma.
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| Overall design |
set 1: 24 tumor samples analyzed
set 2: 9 hyperplastic ganglia harvested at 3 time points (day 0, day 7 and day 14) and 2 tumors "small" size were analysed
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| Contributor(s) |
Balamuth NJ, Wood A, Wang Q, Jagannathan J, Zhang Z, Chen Z, Mayes P, Rappaport E, Pawel B, Weber B, Wooster R, Sekyere E, Marshall G, Maris JM |
| Citation(s) |
20233875 |
| Submission date |
Aug 20, 2009 |
| Last update date |
Mar 21, 2012 |
| Contact name |
Jayanti Jagannathan |
| E-mail(s) |
jagannathan@email.chop.edu
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| Phone |
2674262286
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| Organization name |
Childrens Hospital of Philadelphia
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| Department |
Oncology
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| Street address |
34th & Civic center blvd
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| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (1) |
| GPL2995 |
ABI Mouse Genome Survey Microarray |
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| Samples (35)
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| Relations |
| BioProject |
PRJNA118369 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE17740_Filt_Norm_tumor data.txt.gz |
2.5 Mb |
(ftp)(http) |
TXT |
| GSE17740_ganglia_normalized_geo.txt.gz |
751.7 Kb |
(ftp)(http) |
TXT |
| GSE17740_readme.txt |
66 b |
(ftp)(http) |
TXT |
| Processed data are available on Series record |
| Processed data provided as supplementary file |
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