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Published on: December 9, 2016
Identification of New Chemoresistance-Associated Genes in Triple-Negative Breast Cancer by Single-Cell Transcriptomic
Spyros Foutadakis1, Dimitrios Kordias2,3, Giannis Vatsellas1
1Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece.
Abstract:
Triple-negative breast cancer (TNBC) is a particularly aggressive mammary neoplasia with a high fatality rate, mainly because of the development of resistance to administered chemotherapy, the standard treatment for this disease. In this study, we employ both bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) to investigate the transcriptional landscape of TNBC cells cultured in two-dimensional monolayers or three-dimensional spheroids, before and after developing resistance to the chemotherapeutic agents paclitaxel and doxorubicin. Our findings reveal significant transcriptional heterogeneity within the TNBC cell populations, with the scRNA-seq identifying rare subsets of cells that express resistance-associated genes not detected by the bulk RNA-seq. Furthermore, we observe a partial shift towards a highly mesenchymal phenotype in chemoresistant cells, suggesting the epithelial-to-mesenchymal transition (EMT) as a prevalent mechanism of resistance in subgroups of these cells. These insights highlight potential therapeutic targets, such as the PDGF signaling pathway mediating EMT, which could be exploited in this setting. Our study underscores the importance of single-cell approaches in understanding tumor heterogeneity and developing more effective, personalized treatment strategies to overcome chemoresistance in TNBC.
Insights
Single-cell sequencing reveals rare triple-negative breast cancer cells driving chemoresistance. Identifying these cells and pathways like EMT offers new targets for personalized treatments against this aggressive cancer.
Area of Science:
- Oncology
- Genomics
- Cell Biology
Background:
- Triple-negative breast cancer (TNBC) is aggressive with poor outcomes due to chemotherapy resistance.
- Current treatments face challenges from developing drug resistance in TNBC.
- Understanding TNBC heterogeneity is crucial for improving therapeutic strategies.
Purpose of the Study:
- To investigate the transcriptional differences in TNBC cells before and after developing chemoresistance.
- To compare bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) in identifying resistance mechanisms.
- To uncover novel therapeutic targets for overcoming chemoresistance in TNBC.
Main Methods:
- Bulk RNA-sequencing and scRNA-seq were performed on TNBC cells.
- Cells were cultured in 2D monolayers and 3D spheroids.
- Resistance was induced using paclitaxel and doxorubicin.
Main Results:
- Significant transcriptional heterogeneity was observed in TNBC populations.
- scRNA-seq identified rare chemoresistant cell subsets missed by bulk sequencing.
- Chemoresistant cells showed a partial shift towards a mesenchymal phenotype, indicating EMT.
Conclusions:
- Single-cell approaches are vital for dissecting tumor heterogeneity and identifying rare resistant cells.
- The epithelial-to-mesenchymal transition (EMT) is a key mechanism of chemoresistance in TNBC subgroups.
- Targeting pathways like PDGF signaling, involved in EMT, may offer new therapeutic avenues for TNBC.
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