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Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [Hi-C]

ABSTRACT: Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [Hi-C]

PROVIDER: PRJNA831779 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18911071_1.fastq.gz	Fastqsanger.gz
	SRR18911071_2.fastq.gz	Fastqsanger.gz
	SRR18911072_1.fastq.gz	Fastqsanger.gz
	SRR18911072_2.fastq.gz	Fastqsanger.gz
	SRR18911073_1.fastq.gz	Fastqsanger.gz

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Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [Hi-C]

Project description:Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. However, little is known about the rewiring of the 3D chromatin landscape during cancer progression to a chemotherapy-resistant state. We utilized a patient-derived xenograft (PDX) mouse model of triple-negative breast cancer (UCD52) to characterize changes in the 3D structure between the primary tumor and carboplatin-resistant state. Systematic integration of matched chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing data revealed a widespread increase in short-range (<2Mb) interactions with the corresponding increase in chromatin looping and topologically associating domain (TAD) formation, chromatin state switching into a more active state, large-scale deletions, amplification of ATP-binding cassette (ABC) transporters and nearly complete shutdown of drug metabolism pathways. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of many aggressiveness-, metastasis- and other cancer-related pathways. Transcriptome changes suggest the role of downregulated protein-coding genes and upregulated long-noncoding RNAs in drug resistance. Integrative analysis confirmed increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial metabolic processes. Our results highlight that 3D genome remodeling may be a key mechanism underlying drug resistance.

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Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [RNA-Seq]

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Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft

Project description:Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft

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Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [RNA-Seq]

Project description:Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [RNA-Seq]

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LC-MS/MS identification of differentially expressed proteins in carboplatin resistant Triple Negative Breast Cancer

Project description:Triple negative breast cancer (TNBC) is the subtype of breast cancer most lacking in efficient treatment options. Although many TNBCs show remarkable responses to carboplatin-based chemotherapy, they often develop resistance over time. With increasing use of carboplatin in clinics, there is a pressing need to understand mechanisms causing carboplatin resistance and identify the vulnerabilities of carboplatin-resistant tumors. We generated carboplatin-resistance models based on the TNBC cell line MDA-MB-468 and patient derived xenograft (PDX) models of TNBCs. By combining the results of mass spectrometry-based proteome profiling and a kinome RNA interference screen, we assessed the molecular changes and vulnerabilities of carboplatin-resistant TNBCs. Using pharmacological inhibition of the identified targets, we validated the dependencies of carboplatin-resistant cells in vitro and in PDX models. We found that carboplatin resistance in TNBC is accompanied by drastic proteome rewiring. Carboplatin-induced metabolism alterations and upregulation of anti-oxidative response keep low levels of DNA damage and support cell replication in the presence of carboplatin. Carboplatin-resistant cells also exhibited longer mitosis due to dysregulation of mitotic checkpoint. Whereas the components of the mitotic checkpoints, AURKA and BUB1, are essential for the viability of carboplatin-resistant cells, the checkpoint kinases CHEK1 and WEE1 are indispensable for survival of carboplatin-treated resistant cells. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Abrogation of the mitotic checkpoint re-sensitizes carboplatin-resistant TNBCs to carboplatin. CHEK1 inhibition represents a potential strategy for the treatment of carboplatin-resistant TNBCs.

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Gene expression in NIH:OVCAR-3 xenograft tumor treated with vehicle or carboplatin [Progression]

Project description:Gene expression differences in OVCAR3 xenograft tumors after vehicle or carboplatin treatment were successfully identified

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Project description:Triple-negative breast cancer (TNBC) is malignant cancer with a high risk of recurrence. To date, the underlying 3D chromatin organizations of TNBC have remained unclear. Here, using in situ Hi-C, we characterized the 3D chromatin organizations in cells representing five distinct subtypes of breast cancer (including TNBC) and TNBC tissues, compared to normal cells/tissues. We found that the global and local 3D architectures are severely disrupted in TNBC cells. Importantly, we detected CTCF-dependent TNBC-susceptible loss/gain of 3D chromatin organizations and found that these changes were strongly associated with perturbed chromatin accessibility and transcriptional dysregulations. Although some discrepancies exist between TNBC cell lines and tissues, we observed that perturbed local 3D architectures found in TNBC cells are partially conserved in TNBC tissues. Furthermore, we discovered distinct tissue-specific chromatin loops by comparing normal and TNBC tissues. Collectively, our findings provide important features of 3D chromatin organization in TNBC.

2022-05-06 | GSE167150 | GEO

Proteomic landscapes of 3D and 2D models of High-Grade Serous Ovarian Carcinoma: Implications for Carboplatin Response

Project description:High-Grade Serous Ovarian Carcinoma (HGSOC) is is the most common form of ovarian cancer and finding new treatments remains an unmet need. While drug discovery is typically performed in two-dimensional (2D) monolayers, three-dimensional (3D) culture systems better mimic in vivo conditions. However, a comprehensive comparison of 3D vs 2D ovarian cancer models is lacking. Here, we quantitatively compared the whole cell proteomic signatures of 4 ovarian cell lines—PEO1, PEO4, UWB1.289, and UWB1.289+BRCA1— with different status of BRCA genes grown, in 2D and in 3D. Using isobaric labeling proteomics, we quantified 6,668 proteins and identified 412 significantly altered proteins between 2D and 3D. Proteins upregulated in 3D were enriched for transmembrane transport and oxidoreductase activity, while energy metabolism and cell growth pathways also showed dimensionality-dependent changes. Notably, membrane-associated proteins such as EGFR were downregulated in spheroids, particularly in PEO1 and PEO4. Furthermore, 3D culture modulated the response to carboplatin, with increased expression of drug resistance-associated proteins, including NDUF family members and ATP6V0A2, in all spheroid models. These findings underscore how culture dimensionality influences both the molecular landscape and chemotherapeutic response of HGSOC cells and highlight candidate targets for overcoming carboplatin resistance.

2025-10-13 | PXD062934 | Pride

Proteomic landscapes of 3D and 2D models of High-Grade Serous Ovarian Carcinoma: Implications for Carboplatin Response

Project description:High-Grade Serous Ovarian Carcinoma (HGSOC) is the most common form of ovarian cancer and finding new treatments remains an unmet need. While drug discovery is typically performed in two-dimensional (2D) monolayers, three-dimensional (3D) culture systems better mimic in vivo conditions. However, a comprehensive comparison of 3D vs 2D ovarian cancer models is lacking. Here, we quantitatively compared the whole cell proteomic signatures of 4 ovarian cell lines—PEO1, PEO4, UWB1.289, and UWB1.289+BRCA1— with different status of BRCA genes grown, in 2D and in 3D. Using isobaric labeling proteomics, we quantified 6,404 proteins and identified 371 significantly and commonly altered proteins between 2D and 3D. Proteins upregulated in 3D were enriched for transmembrane transport and NADH:ubiquinone oxidoreductase Complex I, while energy metabolism and cell growth pathways also showed dimensionality-dependent changes. Notably, membrane-associated proteins were downregulated in spheroids, particularly EGFR in PEO1. Furthermore, 3D culture modulated the response to carboplatin, with increased expression of drug resistance-associated proteins, including NDUF family members in all spheroid models. These findings underscore how culture dimensionality influences both the molecular landscape and chemotherapeutic response of HGSOC cells and highlight candidate targets for overcoming carboplatin resistance.

2025-10-13 | PXD066652 | Pride

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