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Nat Commun. 2018 Sep 4;9(1):3588. doi: 10.1038/s41467-018-06052-0.

Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq.

Author information

1
Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
2
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
3
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02215, USA.
4
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
5
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
6
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
7
Department of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
8
The Broad Institute of Harvard and MIT, Cambridge, MA, 02139, USA.
9
The Ludwig Center at Harvard, Boston, MA, 02215, USA.
10
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA. michor@jimmy.harvard.edu.
11
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02215, USA. michor@jimmy.harvard.edu.
12
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA. michor@jimmy.harvard.edu.
13
The Broad Institute of Harvard and MIT, Cambridge, MA, 02139, USA. michor@jimmy.harvard.edu.
14
The Ludwig Center at Harvard, Boston, MA, 02215, USA. michor@jimmy.harvard.edu.
15
Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, 02115, USA. michor@jimmy.harvard.edu.
16
Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. lellisen@mgh.harvard.edu.

Abstract

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.

PMID:
30181541
PMCID:
PMC6123496
DOI:
10.1038/s41467-018-06052-0
[Indexed for MEDLINE]
Free PMC Article

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