PXD065282-1

PXD065282 is an original dataset announced via ProteomeXchange.

Title	Chromosome 8 gain drives cancer progression by hijacking the translational regulator 4E-BP1 sensitizing for targeted CDK4/6 inhibition
Description	Chromosome 8 (chr8) gains are common in cancer. However, their potential contribution to tumor heterogeneity is largely unexplored. Ewing sarcoma (EwS) is characterized by pathognomonic FET::ETS fusions but a general paucity of other recurrent somatic mutations that could explain the observed clinical diversity. In EwS, chr8 gains are the second most common genetic alteration rendering EwS an ideal model to investigate the relevance of chr8 gains in an otherwise silent genomic context. Here, we report that chr8 gain-driven gene expression patterns correlate with poor overall survival of EwS patients. This effect is predominantly mediated by increased expression of the translation initiation factor binding protein 4E-BP1 encoded by EIF4EBP1 on chr8. High EIF4EBP1 expression showed the strongest association with poor patient survival among all chr8-encoded genes and correlated with chr8 gains in EwS tumors. Similar findings were made in numerous entities of The Cancer Genome Atlas (TCGA). Integrated multi-omics profiling uncovered that 4E-BP1 orchestrates a pro-proliferative proteomic network. Consistently, silencing of 4E-BP1 in the EwS model reduced cell proliferation, clonogenicity, spheroidal growth in vitro, and tumor growth in vivo. Drug screens and functional assays revealed that high 4E-BP1 expression sensitizes for pharmacological CDK4/6-inhibition in preclinical models. Collectively, we establish chr8 gains and high 4E-BP1 expression as prognostic biomarkers in EwS and demonstrate that their association with patient outcome is primarily mediated by 4E-BP1 orchestrating a pro-proliferative proteomic network sensitizing EwS for CDK4/6-inhibitors. Our data suggest that testing for chr8 gains may improve risk-stratification and therapeutic management in EwS and other cancers.
HostingRepository	PRIDE
AnnounceDate	2025-09-23
AnnouncementXML	Submission_2025-09-23_06:33:14.028.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Karim Aljakouch
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	6x(13)C; 6x(13)C; homoserine; 6x(13)C labeled L-arginine; iodoacetamide derivatized residue
Instrument	timsTOF Pro; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-20 20:45:11	ID requested
⏵ 1	2025-09-23 06:33:14	announced

10.1101/2022.12.11.519935;

submitter keyword: Chromosome 8 gain, 4E-BP1 Ewing sarcoma, CDK4/6 inhibitor, chromosome 8 amplification, chromosome 8 copy number variation, EIF4EBP1

Prof. Dr. Jeroen Krijgsveld
contact affiliation	German Cancer Research Center (DKFZ), Heidelberg, Germany Heidelberg University, Medical Faculty, Heidelberg, Germany
contact email	j.krijgsveld@dkfz.de
lab head
Karim Aljakouch
contact affiliation	DKFZ
contact email	karim.aljakouch@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD065282
     1. Label: PRIDE project
     2. Name: Chromosome 8 gain drives cancer progression by hijacking the translational regulator 4E-BP1 sensitizing for targeted CDK4/6 inhibition