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TNBC Drug Resistance

ABSTRACT: Background Development of drug resistance is often dynamic and requires time series experiments to understand these processes. The most abundant source of information regarding such progressive activity is tracking single cell gene expression data. Our understanding of the imminent role of phenotype switching in modifying therapeutic response has considerably increased.The analysis of single cell transcriptomic data along with machine learning models offers a constructive tool to describe dynamic cellular processes to elucidate cell-to-cell variability within the population after drug exposure. Here we studied how genomic and non-genomic basis for transcriptome differences can influence the developing drug resistance and clonal fitness. Results: This study describes the scRNA-seq analysis of untreated, treated and drug holiday PDX transplants of TNBC exposed to platinum. This builds from the materials and findings of our paper by Salehi, Kabeer et al, Nature 2021 (PMID: 3416307), in which we established the measurement of fitness in this time series. In the new work, we have mapped single cell transcription in conjunction, allowing a dissection of copy number driven (in-cis) clonal transcription and non-clonal, ie non-genomic transcription. We developed an experimental and computational platform consisting of four major steps: (1) timeseries sampling of scRNA-seq 126,556 TNBC PDX cells >2.5 years; (2) clustering the tumor cells into groups reflecting their drug sensitivity, resistance and other characteristics; (3) performing trajectory inference to identify lineages of transitional processes along with drug and tumor progression; (4) estimating the longitudinal gene expression of each lineage; and identifying significant genes between-lineage differential expression modules. Interestingly, we identified a small group of genes (18.9%) that display a new cell state that is not towards the untreated (Un-Rx) nor towards treated Rx which are distant from untreated cell states. The pathway results are shared between two different quantitative measurements of clone-aware differential expression and pseudotime analysis.

PROVIDER: EGAS00001007242 | EGA |

REPOSITORIES: EGA

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Project description:Background: Current protocols for the treatment of ovarian cancer include combination chemotherapy with a platinating agent and a taxane. However, many patients experience relapse of their cancer and the development of drug resistance is not uncommon, making successful second line therapy difficult to achieve. The objective of this study was to develop a cell line resistant to both carboplatin and docetaxel (dual drug resistant ovarian cell line A2780CBNDXL), along with single agent resistant lines (docetaxel resistant A2780DXL and carboplatin resistant A2780CBN), to investigate the mechanisms which underlie the development of dual drug resistance. Methods: The A2780 epithelial ovarian cancer cell line was used to select for isogenic carboplatin, docetaxel and dual drug resistant cell lines. A selection method of gradually increasing drug doses was implemented to avoid clonal selection. Resistance was confirmed using a clonogenic assay. Changes in gene expression associated with the development of drug resistance were determined by microarray analysis compared to parental co-culture control A2780CC. Changes in selected genes were validated by QPCR and immunoblotting. Results: Three isogenic cell lines were developed and resistance to each drug or the combination of drugs was confirmed. Development of resistance was accompanied by a reduced growth rate. The microarray and QPCR analyses showed that unique changes in gene expression occurred in the dual drug resistant cell line and that genes known to be involved in resistance could be identified in all cell lines. Conclusions: Novel changes in gene expression can occur in the development of dual drug resistance, indicating that dual drug resistance is not a simple combination of the changes occurring in single agent resistance Carboplatin, docetaxel (GSE26129) and carboplatin/docetaxel dual resistant cell lines of ovarian A2780 were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with two replicate of both forward and reverse labellings for each cell line. Four arrays were used for this experiments. And it was four replicate of both forward and reverse labellings for A2780 cells. Eight arrays were used for this experiments

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TNBC Drug Resistance

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