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

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

PROVIDER: PRJNA831784 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18911309_1.fastq.gz	Fastqsanger.gz
	SRR18911309_2.fastq.gz	Fastqsanger.gz
	SRR18911310_1.fastq.gz	Fastqsanger.gz
	SRR18911310_2.fastq.gz	Fastqsanger.gz
	SRR18911311_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 [RNA-Seq]

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 [Hi-C]

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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 [Hi-C]

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

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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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Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograft.

Project description:Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin state switching, leading to oncogene expression and silencing of tumor suppressors. However, little is known about 3D changes during cancer progression to a chemotherapy-resistant state. We integrated chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing obtained from triple-negative breast cancer patient-derived xenograft primary tumors (UCD52) and carboplatin-resistant samples and found increased short-range (< 2 Mb) interactions, chromatin looping, formation of TAD, chromatin state switching into a more active state, and amplification of ATP-binding cassette transporters. Transcriptome changes suggested the role of long-noncoding RNAs in carboplatin resistance. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of aggressiveness-, metastasis- and other cancer-related pathways. Integrative analysis highlighted increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial energy metabolism. Our results suggest that 3D genome remodeling may be a key mechanism underlying carboplatin resistance.

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