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Phenotypic consequences of SLC25A40-ABCB1 fusions beyond drug resistance in High Grade Serous Ovarian Cancer

ABSTRACT: Phenotypic consequences of SLC25A40-ABCB1 fusions beyond drug resistance in High Grade Serous Ovarian Cancer

PROVIDER: PRJNA759615 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15689058_1.fastq.gz	Fastqsanger.gz
	SRR15689058_2.fastq.gz	Fastqsanger.gz
	SRR15689059_1.fastq.gz	Fastqsanger.gz
	SRR15689059_2.fastq.gz	Fastqsanger.gz
	SRR15689060_1.fastq.gz	Fastqsanger.gz

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Phenotypic consequences of SLC25A40-ABCB1 fusions beyond drug resistance in High Grade Serous Ovarian Cancer

Project description:Purpose: Our laboratory recently identified the most common mechanism of acquired drug resistance in High Grade Serous Ovarian Cancer (HGSOC) to date, SLC25A40-ABCB1 fusions. The primary aim of this study was to examine the transcriptional profile of drug resistant fusion-positive SLC25A40-ABCB1 fusion positive cells. Single cell fusion-positive and negative clones were derived from the human HGSOC cell line AOCS-18.5 Methods: Three independent replicates of RNA was collected from five SLC25A40-ABCB1 fusion-negative AOCS 18.5 clones (B,C, D,E,F) and five SLC25A40-ABCB1 fusion-positive AOCS 18.5 clones (8,9,13, 15B, 18B) and submitted for NextSeq 100bp paired-end, polyA RNA-sequencing. Cells were collected 48-72hrs post seeding. 20 million paired end reads per sample were generated. Reads were mapped to the human reference GRCh37.92 using the STAR two pass method (v2.6.0b). Counts were generated on the ensemble release GRCh37.92 GTF annotation using HTSeq (v0.10.0). Counts were normalized to logged TMM values using edgeR (v3.28.1). TPM expression values were also generated. Differential gene expression analysis was performed using DESeq2 (v1.26.0) on the raw counts. In all, 3333 genes were significantly upregulated (>1.5 log2 fold change, p-adj<0.1) in fusion-positive lines, with 1751 genes significantly downregulated Conclusions: Using a stringent cut-off of >2.0 fold change (n=2238 differentially expressed genes), Metascape pathway analysis revealed that the most significantly enriched pathways in fusion-positive clones included the NABA matrisome associated pathway (160/751 genes, 7.24%), followed by external encapsulating structure organization (102/398 genes, 4.62%) and regulation of cell adhesion (139/734 genes, 6.29%).

2021-09-03 | GSE183210 | GEO

Phenotypic Consequences of SLC25A40-ABCB1 Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer.

Project description:Despite high response rates to initial chemotherapy, the majority of women diagnosed with High-Grade Serous Ovarian Cancer (HGSOC) ultimately develop drug resistance within 1-2 years of treatment. We previously identified the most common mechanism of acquired resistance in HGSOC to date, transcriptional fusions involving the ATP-binding cassette (ABC) transporter ABCB1, which has well established roles in multidrug resistance. However, the underlying biology of fusion-positive cells, as well as how clonal interactions between fusion-negative and positive populations influences proliferative fitness and therapeutic response remains unknown. Using a panel of fusion-negative and positive HGSOC single-cell clones, we demonstrate that in addition to mediating drug resistance, ABCB1 fusion-positive cells display impaired proliferative capacity, elevated oxidative metabolism, altered actin cellular morphology and an extracellular matrix/inflammatory enriched transcriptional profile. The co-culture of fusion-negative and positive populations had no effect on cellular proliferation but markedly altered drug sensitivity to doxorubicin, paclitaxel and cisplatin. Finally, high-throughput screening of 2907 FDA-approved compounds revealed 36 agents that induce equal cytotoxicity in both pure and mixed ABCB1 fusion populations. Collectively, our findings have unraveled the underlying biology of ABCB1 fusion-positive cells beyond drug resistance and identified novel therapeutic agents that may significantly improve the prognosis of relapsed HGSOC patients.

| S-EPMC8616176 | biostudies-literature

Targeted nanopore sequencing for the identification of ABCB1 promoter translocations in relapsed acute myeloid leukemia [RNAseq]

Project description:Resistance to chemotherapy is the most common cause of treatment failure in acute myeloid leukemia and the drug efflux pump ABCB1 is a critical mediator. Here we demonstrate that in vitro daunorubicin exposure can induce activating ABCB1 promoter translocations in human myeloid cells, similar to those recently described in recurrent high-grade serous ovarian and breast cancer. We then develop a targeted nanopore sequencing approach that enables efficient identification of ABCB1 structural variants in high-grade serous ovarian cancer. Finally, we confirm that ABCB1high cases of relapsed AML are not characterized by ABCB1 promoter translocations but instead show high-level activity of native promoters, consistent with endogenous regulation.

2020-10-22 | GSE159391 | GEO

Targeted nanopore sequencing for the identification of ABCB1 promoter translocations in relapsed acute myeloid leukemia [Nanopore]

2020-10-22 | GSE159324 | GEO

Targeted nanopore sequencing for the identification of ABCB1 promoter translocations in relapsed acute myeloid leukemia [4C-seq]

2020-10-22 | GSE159394 | GEO

Targeted nanopore sequencing for the identification of ABCB1 promoter translocations in relapsed acute myeloid leukemia [Targeted Resequencing]

2020-10-22 | GSE159331 | GEO

Targeted nanopore sequencing for the identification of ABCB1 promoter translocations in relapsed acute myeloid leukemia [ChIP-seq]

2020-10-22 | GSE159317 | GEO

Gene expression profiling of ABCB1 positive and ABCB1 negative OCM1A cells

Project description:Gene expression profiling of ABCB1 positive and ABCB1 negative OCM1A cells. ABCB1 is an ATP-dependent transporter efflux pump. OCM1A cell line is derived from uveal melanomas. 6 samples (3 ABCB1 positive and 3 ABCB1 negative) from 3 independent ABCB1 shift assays were analysed

2010-09-01 | E-GEOD-21425 | biostudies-arrayexpress

Gene expression profiling of ABCB1 positive and ABCB1 negative OCM1A cells

Project description:Gene expression profiling of ABCB1 positive and ABCB1 negative OCM1A cells. ABCB1 is an ATP-dependent transporter efflux pump. OCM1A cell line is derived from uveal melanomas.

2010-09-01 | GSE21425 | GEO

Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer.

Project description:ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. Here we report that ovarian and breast samples from chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1, placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1, as well as patients with multiple distinct fusion events. The partner gene selected depended on its structure, promoter strength, and chromosomal proximity to ABCB1. Fusion positivity was strongly associated with the number of lines of MDR1-substrate chemotherapy given. MDR1 inhibition in a fusion positive ovarian cancer cell line increased sensitivity to paclitaxel more than 50-fold. Convergent evolution of ABCB1 fusion is therefore frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi.

| S-EPMC6426934 | biostudies-literature

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