PXD022934
PXD022934 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | PTEN DEFICIENCY LEADS TO PROTEASOME ADDICTION, A NOVEL VULNERABILITY IN GLIOBLASTOMA |
Description | Glioblastoma (GBM) is the most common primary brain tumor in adults with a median survival of approximately 15 months, therefore, more effective treatment options for GBM are required. To identify new drugs targeting glioblastomas, we performed a high throughput drug screen using patient-derived neurospheres cultured to preferentially retain their glioblastoma stem cell (GSC) phenotype. High throughput drug screening was performed on GSCs followed by a second dose response assay of the 5 identified original hits. A PI3K/mTOR dependency to a proteasome inhibitor (carfilzomib), was confirmed by gain of function and loss of function experiments. Proteasome inhibition response signatures were derived from proteomic and bioinformatic analysis. Molecular mechanism of action was determined using in vitro 3-dimensional (3D) GBM organoid models and in vivo preclinical orthotopic GBM models. We found that GSCs were highly sensitive to proteasome inhibition due to an underlying dependency on an increased protein synthesis rate, and loss of autophagy, associated with PTEN loss and activation of the PI3K/mTOR pathway. In contrast, combinatory inhibition of autophagy and the proteasome, resulted in enhanced cytotoxicity specifically in GSCs that did express PTEN. Finally, proteasome inhibition specifically increased cell death markers in 3D glioblastoma organoids, suppressed tumor growth, and increased survival of mice orthotopically engrafted with GSCs. As perturbations of the PTEN/ PI3K axis occur in nearly 50% of GBMs, these findings suggest that a significant fraction of these tumors could be vulnerable to proteasome inhibition. |
HostingRepository | MassIVE |
AnnounceDate | 2021-01-24 |
AnnouncementXML | Submission_2021-01-24_19:55:11.xml |
DigitalObjectIdentifier | |
ReviewLevel | Non peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Alexandre Rosa Campos |
SpeciesList | scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
ModificationList | Oxidation |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2020-12-04 13:32:54 | ID requested | |
⏵ 1 | 2021-01-24 19:55:12 | announced |
Publication List
no publication |
Keyword List
submitter keyword: Glioblastoma, proteasome, PTEN, organoids, neurospheres |
Contact List
Frank Furnari | |
---|---|
contact affiliation | University of California San Diego |
contact email | ffurnari@ucsd.edu |
lab head | |
Alexandre Rosa Campos | |
contact affiliation | SBP Medical Discovery Institute |
contact email | arosacampos@sbpdiscovery.org |
dataset submitter |
Full Dataset Link List
MassIVE dataset URI |
Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://massive.ucsd.edu/MSV000086560/ |