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PXD022934

PXD022934 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitlePTEN DEFICIENCY LEADS TO PROTEASOME ADDICTION, A NOVEL VULNERABILITY IN GLIOBLASTOMA
DescriptionGlioblastoma (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.
HostingRepositoryMassIVE
AnnounceDate2021-01-24
AnnouncementXMLSubmission_2021-01-24_19:55:11.xml
DigitalObjectIdentifier
ReviewLevelNon peer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterAlexandre Rosa Campos
SpeciesList scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationListOxidation
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-12-04 13:32:54ID requested
12021-01-24 19:55:12announced
Publication List
no publication
Keyword List
submitter keyword: Glioblastoma, proteasome, PTEN, organoids, neurospheres
Contact List
Frank Furnari
contact affiliationUniversity of California San Diego
contact emailffurnari@ucsd.edu
lab head
Alexandre Rosa Campos
contact affiliationSBP Medical Discovery Institute
contact emailarosacampos@sbpdiscovery.org
dataset submitter
Full Dataset Link List
MassIVE dataset URI
Dataset FTP location
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