PXD037015-1

PXD037015 is an original dataset announced via ProteomeXchange.

Title	Targeting tumor-intrinsic neural vulnerabilities of glioblastoma
Description	The neural behavior of glioblastoma, including the formation of tumor microtubes and synaptic circuitry, is increasingly understood to be pivotal for disease manifestation (Osswald et al. 2015; Venkatesh et al. 2015; Weil et al. 2017; Venkataramani et al. 2019; Venkatesh et al. 2019; Alcantara Llaguno et al. 2019; Venkataramani et al. 2022). Nonetheless, the few approved treatments for glioblastoma target its oncological nature, while its neural vulnerabilities remain incompletely mapped and clinically unexploited. Here, we systematically survey the neural molecular dependencies and cellular heterogeneity across 27 glioblastoma patients and diverse model systems. In patient tumor samples taken directly after surgery, we identify a spectrum of neural stem cell morphologies indicative of poor prognosis, and discover a set of repurposable neuroactive drugs with unexpected and consistent anti-glioma efficacy. Glioblastoma cells exhibit functional dependencies on highly expressed drug targets including neurological ion channels and receptors, while interpretable molecular machine learning reveals downstream convergence on secondary drug targets (COSTAR) involving AP-1-driven tumor suppression. COSTAR enables in silico drug screening on >1 million compounds that are validated with high accuracy. Multi-omic profiling of drug-treated glioblastoma cells confirms rapid Ca2+-driven AP-1 pathway induction to represent a tumor-intrinsic vulnerability at the intersection of oncogenesis and neural activity-dependent signaling. Finally, the consistent anti-glioma activity across patients and model systems is epitomized by the antidepressant Vortioxetine, which synergizes in vivo with approved glioblastoma chemotherapies. In all, our global analysis reveals that the neural vulnerabilities of glioblastoma converge on an AP-1 mediated gene regulatory network with direct translatable potential.
HostingRepository	PanoramaPublic
AnnounceDate	2024-08-01
AnnouncementXML	Submission_2024-08-01_11:20:57.337.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Sandra Goetze
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	Label:13C(6)15N(4); mTRAQ:13C(6)15N(2)
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2022-09-26 15:31:32	ID requested
⏵ 1	2024-08-01 11:20:57	announced

no publication

submitter keyword: pharmacoscopy, glioblastoma, TP53, BTG1

Bernd Wollscheid
contact affiliation	ETHZ
contact email	bernd.wollscheid@hest.ethz.ch
lab head
Sandra Goetze
contact affiliation	ETHZ
contact email	sgoetze@ethz.ch
dataset submitter

Panorama Public dataset URI