Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq.
Mihriban KaraayvazSimona CristeaShawn M GillespieAnoop P PatelRavindra MylvaganamChristina C LuoMichelle C SpechtBradley E BernsteinFranziska MichorLeif W EllisenPublished in: Nature communications (2018)
Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by extensive intratumoral heterogeneity. To investigate the underlying biology, we conducted single-cell RNA-sequencing (scRNA-seq) of >1500 cells from six primary TNBC. Here, we show that intercellular heterogeneity of gene expression programs within each tumor is variable and largely correlates with clonality of inferred genomic copy number changes, suggesting that genotype drives the gene expression phenotype of individual subpopulations. Clustering of gene expression profiles identified distinct subgroups of malignant cells shared by multiple tumors, including a single subpopulation associated with multiple signatures of treatment resistance and metastasis, and characterized functionally by activation of glycosphingolipid metabolism and associated innate immunity pathways. A novel signature defining this subpopulation predicts long-term outcomes for TNBC patients in a large cohort. Collectively, this analysis reveals the functional heterogeneity and its association with genomic evolution in TNBC, and uncovers unanticipated biological principles dictating poor outcomes in this disease.
Keyphrases
- single cell
- rna seq
- copy number
- gene expression
- mitochondrial dna
- genome wide
- dna methylation
- high throughput
- end stage renal disease
- ejection fraction
- induced apoptosis
- chronic kidney disease
- newly diagnosed
- peritoneal dialysis
- public health
- cell cycle arrest
- oxidative stress
- cell death
- type diabetes
- glycemic control
- signaling pathway
- endoplasmic reticulum stress
- replacement therapy
- smoking cessation
- cell adhesion
- weight loss