Molecular profiling and specific targeting of gemcitabine-resistant subclones in heterogeneous pancreatic cancer cell populations
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ABSTRACT:
PROVIDER: PRJNA972711 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24564847_1.fastq.gz | Fastqsanger.gz | |||
| SRR24564847_2.fastq.gz | Fastqsanger.gz | |||
| SRR24564848_1.fastq.gz | Fastqsanger.gz | |||
| SRR24564848_2.fastq.gz | Fastqsanger.gz | |||
| SRR24564849_1.fastq.gz | Fastqsanger.gz |
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Project 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.
2023-09-19 | PXD042256 | Pride
Project 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. 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.
2023-05-20 | GSE232549 | GEO
Project description:We generated gemcitabine resistant subclones from the human pancreatic cancer cell line BxPC3 using chronic low dose exposure to gemcitabine. Three gemcitabine resistant subclones (BxGR-80C, BxGR-120C and BxGR-360C) were sequenced in addition to BxPC3 cells.
2021-12-21 | E-MTAB-11186 | biostudies-arrayexpress
Project description:PurposeChemotherapy is pivotal in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC). Technical advances unveiled a high degree of inter- and intratumoral heterogeneity. We hypothesized that intratumoral heterogeneity (ITH) impacts response to gemcitabine treatment and demands specific targeting of resistant subclones.MethodsUsing single cell-derived cell lines (SCDCLs) from the classical cell line BxPC3 and the basal-like cell line Panc-1, we addressed the effect of ITH on response to gemcitabine treatment.ResultsIndividual SCDCLs of both parental tumor cell populations showed considerable heterogeneity in response to gemcitabine. Unsupervised 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 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. We used recursive feature elimination for Feature Selection in order to compute sets of proteins that showed strong association with the response to gemcitabine. The optimal protein set calculated for Panc-1 comprised fewer proteins in comparison to the protein set determined for 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.ConclusionOur model system of SCDCLs identified gemcitabine-resistant subclones and provides evidence for the critical role of ITH for treatment response in PDAC. We exploited molecular differences as the basis for differential response and used these for more targeted therapy of resistant subclones.
| S-EPMC10502231 | biostudies-literature
Project description:This experiment describes the differential microRNA expression between parental gemcitabine-sensitive BxPC-3 cells and their resistant subclones, Bx-GEM. To select for the resistant subclones, parental BxPC-3 cells were treated with increasing concentrations of gemcitabine (10, 25, 50, 100 and 200 nM) for more than one year. Cells resistant at each stage of drug dosing were re-cultured in the subsequent dose, and their resistance confirmed via cell viability assays. Subclones resistant to 200 nM gemcitabine, in additon to the parental cells were used for microRNA profiling by array. Total RNA was extracted from the cells using the miRNeasy Mini Kit (Qiagen). Fluorescently-labeled miRNA were prepared according to Agilent protocol miRNA Complete Labeling and Hyb Kit. Labeled miRNA sample were hybridized for at least 20 hr at 55C on Agilent human miRNA Microarray Release 19.0, 8x60k. Gene Expression Microarrays were scanned using the Agilent Scanner G2505C.
2017-01-20 | E-MTAB-4927 | biostudies-arrayexpress
Project description:This experiment describes the differential gene expression between parental gemcitabine-sensitive BxPC-3 cells and their resistant subclones, Bx-GEM. To select for the resistant subclones, parental BxPC-3 cells were treated with increasing concentrations of gemcitabine (10, 25, 50, 100 and 200 nM) for more than one year. Cells resistant at each stage of drug dosing were re-cultured in the subsequent dose, and their resistance confirmed via cell viability assays. Subclones resistant to 200 nM gemcitabine, in additon to the parental cells were used for gene profiling by array. Total RNA was extracted from the cells using the miRNeasy Mini Kit (Qiagen). The Illumina TotalPrep RNA Amplification Kit (life technologie) was used to generate single-stranded cRNA from input amounts of 500ng total RNA. 1,5 ug of cRNA were hybridized for 17 hr at 58°C on Illumina human HT12-Microarray using the Standard Illumina Hybridisation Protocol Part # 11322355 (Whole-Genome Gene Expression Direct Hybridization Assay Guide). Gene Expression Microarrays were scanned using the Illumina iScan-Scanner according to the Standard Illumina Scanning Protocol Part # 11322355 (Whole-Genome Gene Expression Direct Hybridization Assay Guide).
2017-01-20 | E-MTAB-4901 | biostudies-arrayexpress
Project description:mRNA-seq of gemcitabine resistant pancreatic cancer cell line subclones derived from BxPC3
| PRJEB48965 | ENA
Project description:Next-generation sequencing was applied to compare the transcriptom of 1) SW1990 human pancreatic cancer cell lines and its gemcitabine-resistant derivative established with long-term exposure in medium containing 100 nM gemcitabine; 2) TRA-1-81+ cells and TRA-1-81- cells isolated from SW1990 human pancreatic cancer cell line.
2017-03-31 | GSE79953 | GEO
Project description:We examined the microarray-based expression profiles of the cells to identify genes associated with gemcitabine resistance
2012-05-09 | GSE35141 | GEO
Project description:The extracellular vesicles (EVs) have become the focus of rising interest, because of their numerous functions in physiology and pathology. Cells release heterogeneous vesicles of different sizes and intracellular origins, including small EVs formed inside endosomal compartments (i.e. exosomes) and EVs of various sizes budding from the plasma membrane. Specific markers for the analysis and isolation of different EV populations are missing, imposing important limitations to understanding EV functions. Here, EVs from human dendritic cells were first separated by their sedimentation speed and then either by their behavior upon upward floatation into iodixanol gradients, or by immuno-isolation. Extensive quantitative proteomic analysis allowing comparison of the isolated populations showed that several classically used exosome markers, like major histocompatibility complex, flotillin and heat shock 70 kDa proteins, are similarly present in all EVs. We identified proteins specifically enriched in small EVs, and define a new set of five protein categories displaying different relative abundance in distinct EV populations. We demonstrate the presence of exosomal and non-exosomal subpopulation within small EVs, and propose their differential separation by immuno-isolation using either CD63, CD81 or CD9. Our work thus provides new guidelines to define subtypes of EVs for future functional studies.
2016-02-11 | PXD003257 | Pride