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In Vivo ORF Overexpression Screening Identifies CCN4 as a Regulator of Glioblastoma Growth Validated Across Multiple
Pushan Dasgupta1,2,3,4
1Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
Despite current multimodal therapies for glioblastoma (GBM), its prognosis remains grim. Thus, a tremendous need exists to identify new genetic drivers that may serve as potential therapeutic targets in glioblastoma (GBM). We describe an in vivo overexpression screening strategy to identify drivers of glioblastoma where we have leveraged TCGA datasets to conduct a functional genomics screen of prioritized open reading frames (ORFs) that are overexpressed and/or amplified in GBM. To interrogate these potential drivers within a more relevant physiological context, the screening was accomplished in vivo in an orthotopic patient-derived glioma stem-like cell (GSC) model. Among 5 positive "hits" from the screen, Cellular Communication Network factor 4 (CCN4) was prioritized for further evaluation. Our functional analyses demonstrated that CCN4 overexpression drives tumor growth in multiple GBM models. Depletion of CCN4 reduced growth in vitro and in vivo and markedly decreased colony formation with the growth phenotype restored upon ectopic expression of CCN4. Structural functional analysis of CCN4 was also conducted. We believe that this screening strategy can serve as a platform for further identification and validation of drivers of GBM.
Insights
Researchers identified Cellular Communication Network factor 4 (CCN4) as a key driver of glioblastoma (GBM) growth. This discovery offers a potential new therapeutic target for this aggressive brain cancer.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Glioblastoma (GBM) exhibits a poor prognosis despite current multimodal treatment strategies.
- Identifying novel genetic drivers is crucial for developing effective glioblastoma therapies.
Purpose of the Study:
- To employ an in vivo overexpression screening strategy to identify novel glioblastoma (GBM) drivers.
- To functionally validate potential GBM drivers within a relevant physiological context.
Main Methods:
- Leveraged The Cancer Genome Atlas (TCGA) datasets to prioritize candidate genes for functional genomics screening.
- Conducted in vivo screening using patient-derived glioma stem-like cell (GSC) models in an orthotopic setting.
- Performed functional analyses including gene depletion and ectopic expression studies.
Main Results:
- Identified five "hits" from the screen, with Cellular Communication Network factor 4 (CCN4) selected for further investigation.
- Demonstrated that CCN4 overexpression promotes tumor growth in multiple GBM models.
- Showed that CCN4 depletion inhibits GBM growth in vitro and in vivo, with restoration of growth upon CCN4 re-expression.
Conclusions:
- The developed screening strategy effectively identifies glioblastoma (GBM) drivers.
- Cellular Communication Network factor 4 (CCN4) is a significant driver of GBM growth and a potential therapeutic target.
- This platform facilitates the discovery and validation of new GBM therapeutic targets.
