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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
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Single-cell decoding of drug induced transcriptomic reprogramming in triple negative breast cancers
Farhia Kabeer1,2, Hoa Tran2, Mirela Andronescu1,2
1Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Genome Biology
|July 18, 2024
Summary
Breast cancer clones with strong platinum resistance show fixed genotypes and minimal transcriptional changes. Weaker clones exhibit dynamic, non-genomic plasticity, contributing to platinum resistance.
Area of Science:
- Oncology
- Genomics
- Transcriptomics
Background:
- Cell intrinsic drug resistance in breast cancer involves genomic and non-genomic variations.
- Somatic copy number (CN) variation drives transcriptional changes and platinum chemotherapy resistance.
- Accurate estimation of clonal fitness from transcriptomic and genomic data is crucial.
Purpose of the Study:
- To identify genomic and transcriptomic mechanisms underlying drug-associated transcriptional cell states in triple-negative breast cancer (TNBC).
- To analyze clonal responses and transcriptional plasticity in TNBC tumors under platinum exposure.
Main Methods:
- Utilized time-series single-cell RNA sequencing (scRNA-seq) data from TNBC patient-derived xenograft (PDX) experiments.
- Co-measured single-cell CN data alongside transcriptomic data.
- Performed pathway analysis and pseudotime analysis to understand transcriptional dynamics.
Main Results:
- Observed distinct clonal responses in TNBC tumors exposed to platinum, with high-fitness clones undergoing sweeps and low-fitness clones showing dynamic transcription.
- Identified epithelial-mesenchymal transition and cytokine signaling pathways as key to resistance.
- Pseudotime analysis revealed hysteresis in transcriptional reversion, indicating new intermediate states upon platinum exposure.
Conclusions:
- Strongly fit clones under platinum maintained fixed genotypes, minimizing transcriptional reversion.
- Weaker clones displayed non-genomic transcriptional plasticity, contributing to platinum resistance.
- Both CN-associated and CN-independent mechanisms influence platinum resistance, impacting treatment strategies.
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