PXD042256

PXD042256 is an original dataset announced via ProteomeXchange.

Title	Molecular profiling and specific targeting of gemcitabine-resistant subclones in heterogeneous pancreatic cancer cell populations
Description	Purpose: Chemotherapy is pivotal in the multimodal treatment of pancreatic cancer patients. In recent years, technical advances have developed experimental methods that unveiled a high degree of inter- and intratumoral heterogeneity in pancreatic cancer. We hypothesized that intratumoral heterogeneity (ITH) impacts response to gemcitabine treatment and demands specific targeting of resistant subclones. Experimental Design: We addressed the effect of ITH on response to gemcitabine treatment using single cell-derived cell lines (SCDCL) from the classical-like cell line BxPC3 and the basal-like cell line Panc-1 which were analyzed by mRNA-seq and mass spectrometry. Results: Individual SCDCLs of the parental tumor cell populations of BxPC3 and Panc-1 showed considerable heterogeneity in response to gemcitabine. Unsupervised principal component analysis (PCA) including the 1,000 most variably expressed genes showed a clustering of the SCDCLs according to their respective sensitivity to gemcitabine treatment for BxPC3, while this clustering was less clear for Panc-1. In BxPC3 SCDCLs, enriched signaling pathways EMT, TNF signaling via NfKB, and IL2STAT5 signaling correlated with more resistant behavior to gemcitabine. In Panc-1 SCDCLs MYC targets V1 and V2 as well as E2F targets were associated with stronger resistance to gemcitabine. Feature extraction of proteomes again identified less proteins whose expression was associated with the response of individual SCDCLs in Panc-1 compared to BxPC3. Based on molecular profiles, we could show that the gemcitabine-resistant SCDCLs of both BxPC3 and Panc-1 are more sensitive to the BET inhibitor JQ1 compared to the respective gemcitabine-sensitive SCDCLs. Conclusions: Our model system of SCDCLs identified gemcitabine-resistant subclones within a parental tumor population and provides evidence for the critical role of ITH for treatment response in pancreatic cancer. Through molecular profiling, we identified specific signaling pathways and protein signatures that might help to explain the differential response to treatment among clones. We exploited these molecular differences for an improved and more targeted therapy of resistant subclones of a heterogeneous tumor.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:05:20.716.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thorben Sauer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2023-05-16 05:15:23	ID requested
1	2023-09-19 06:30:33	announced
⏵ 2	2023-11-14 09:05:29	announced	2023-11-14: Updated project metadata.

F, ä, rber B, Lapshyna O, K, ü, nstner A, Kohl M, Sauer T, Bichmann K, Heckelmann B, Watzelt J, Honselmann K, Bolm L, Ten Winkel M, Busch H, Ungefroren H, Keck T, Gemoll T, Wellner UF, Braun R, Molecular profiling and specific targeting of gemcitabine-resistant subclones in heterogeneous pancreatic cancer cell populations. Front Oncol, 13():1230382(2023) [pubmed]

submitter keyword: treatment response,Pancreatic cancer, intratumor heterogeneity, chemotherapy, gemcitabine

Timo Gemoll
contact affiliation	Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Hospital Schleswig-Holstein, Campus Lübeck, Germany
contact email	timo.gemoll@uni-luebeck.de
lab head
Thorben Sauer
contact affiliation	Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck Germany
contact email	thorben.sauer@student.uni-luebeck.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/2023/09/PXD042256

PRIDE project URI

• PRIDE
  1. PXD042256
     1. Label: PRIDE project
     2. Name: Molecular profiling and specific targeting of gemcitabine-resistant subclones in heterogeneous pancreatic cancer cell populations