PXD036517

PXD036517 is an original dataset announced via ProteomeXchange.

Title	In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance
Description	Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of cancer patients. To gain mechanistic insights, we developed a model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) of acute lymphoblastic leukemia with widely-used cytotoxic drugs for 18 consecutive weeks. In two distinct PDX samples, tumors initially responded to treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, replicate tumors developed different mutations in TP53 and individual sets of chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven by a combination of stochastic and deterministic processes. Transcriptome and proteome showed shared dysregulations between replicate tumors providing putative targets to overcome resistance. In vivo CRISPR/Cas9 dropout screen in PDX revealed broad dependency on BCL2, BRIP1 and COPS2. Accordingly, venetoclax re-sensitized derivative tumors towards chemotherapy, despite genomic heterogeneity, demonstrating direct translatability of the approach. Hence, despite presence of multiple resistanceassociated genomic alterations, effective rescue treatment for polychemotherapyresistant tumors can be identified using functional testing in preclinical models.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:50:29.520.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ashokkumar Jayavelu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-09-05 09:12:23	ID requested
1	2023-01-02 07:30:19	announced
⏵ 2	2023-11-14 07:50:35	announced	2023-11-14: Updated project metadata.

Wirth AK, Wange L, Vosberg S, Henrich KO, Rausch C, Ö, zdemir E, Zeller CM, Richter D, Feuchtinger T, Kaller M, Hermeking H, Greif PA, Senft D, Jurinovic V, Bahrami E, Jayavelu AK, Westermann F, Mann M, Enard W, Herold T, Jeremias I, In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance. Leukemia, 36(12):2863-2874(2022) [pubmed]

submitter keyword: Chemoresistance,Leukemia, Proteome, Drug resistance, PDX

Ashok Kumar Jayavelu
contact affiliation	German Cancer Research Center, Heidelberg
contact email	ak.jayavelu@biochem.mpg.de
lab head
Ashokkumar Jayavelu
contact affiliation	Dept Proteomics and Signal Transduction, MaxPlanck Institute of Biochemistry
contact email	jayavelu@biochem.mpg.de
dataset submitter

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://ftp.pride.ebi.ac.uk/pride/data/archive/2023/01/PXD036517

PRIDE project URI

• PRIDE
  1. PXD036517
     1. Label: PRIDE project
     2. Name: In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance