Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing

Charissa Kim; Ruli Gao; Emi Sei; Rachel Brandt; Johan Hartman; Thomas Hatschek; Nicola Crosetto; Theodoros Foukakis; Nicholas E. Navin

doi:10.1016/j.cell.2018.03.041

Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing

Charissa Kim, Ruli Gao, Emi Sei, Rachel Brandt, Johan Hartman, Thomas Hatschek, Nicola Crosetto, Theodoros Foukakis^*, Nicholas E. Navin

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

688 Scopus citations

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype that frequently develops resistance to chemotherapy. An unresolved question is whether resistance is caused by the selection of rare pre-existing clones or alternatively through the acquisition of new genomic aberrations. To investigate this question, we applied single-cell DNA and RNA sequencing in addition to bulk exome sequencing to profile longitudinal samples from 20 TNBC patients during neoadjuvant chemotherapy (NAC). Deep-exome sequencing identified 10 patients in which NAC led to clonal extinction and 10 patients in which clones persisted after treatment. In 8 patients, we performed a more detailed study using single-cell DNA sequencing to analyze 900 cells and single-cell RNA sequencing to analyze 6,862 cells. Our data showed that resistant genotypes were pre-existing and adaptively selected by NAC, while transcriptional profiles were acquired by reprogramming in response to chemotherapy in TNBC patients. Combination of single-cell DNA and RNA sequencing depicts the evolutionary trajectories of chemoresistance in human triple-negative breast cancer at the genomic and transcriptomic level, highlighting the presence of pre-existing genomic alterations and transcriptional reprogramming of resistant signatures.

Original language	English (US)
Pages (from-to)	879-893.e13
Journal	Cell
Volume	173
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2018.03.041
State	Published - May 3 2018

Funding

This work was supported by grants to N.E.N. from the Lefkofsky Family Foundation , NCI ( 1RO1CA169244-01 ), and the American Cancer Society ( 129098-RSG-16-092-01-TBG ). N.E.N. is a T.C. Hsu Endowed Scholar, AAAS Wachtel Scholar, Andrew Sabin Family Fellow, and Randall Innovator. This study was supported by the MD Anderson Sequencing Core Facility Grant ( CA016672 ) and the Flow Cytometry Facility grant from the NIH ( CA016672 ). The study was also supported by grants from the Breast Cancer Research Foundation ( N013869 ), the Swedish Cancer Society ( CAN 2015/713 ), and the Cancer Society in Stockholm ( 154132 ) to T.F. The study was also supported by a KI-MDACC grant from the Sister Network Institution Fund and GAP program ( 40033 ) at MD Anderson to N.E.N. and the StratCan at the Karolinska Institute to N.C., T.F., and J.H. Additional funding support includes the ALA Fellowship to C.K., Susan Komen Postdoctoral Fellowship ( PDF17487910 ) to R.G., and AACR Basic Cancer Research Fellowship ( 17-40-42-GAO ) to R.G. The PROMIX clinical trial was supported by grants from Roche , the Cancer Society in Stockholm ( 154132, 081141 ), and the Swedish Breast Cancer Association to T.H. We thank Helen Piwnica-Worms, Gloria Echeverria, Funda Meric-Bernstam, Debu Tripathy, Ken Chen, and Russell Broaddus for useful discussions and Sohrab Shah for assistance with software. This work was supported by grants to N.E.N. from the Lefkofsky Family Foundation, NCI (1RO1CA169244-01), and the American Cancer Society (129098-RSG-16-092-01-TBG). N.E.N. is a T.C. Hsu Endowed Scholar, AAAS Wachtel Scholar, Andrew Sabin Family Fellow, and Randall Innovator. This study was supported by the MD Anderson Sequencing Core Facility Grant (CA016672) and the Flow Cytometry Facility grant from the NIH (CA016672). The study was also supported by grants from the Breast Cancer Research Foundation (N013869), the Swedish Cancer Society (CAN 2015/713), and the Cancer Society in Stockholm (154132) to T.F. The study was also supported by a KI-MDACC grant from the Sister Network Institution Fund and GAP program (40033) at MD Anderson to N.E.N. and the StratCan at the Karolinska Institute to N.C., T.F., and J.H. Additional funding support includes the ALA Fellowship to C.K., Susan Komen Postdoctoral Fellowship (PDF17487910) to R.G., and AACR Basic Cancer Research Fellowship (17-40-42-GAO) to R.G. The PROMIX clinical trial was supported by grants from Roche, the Cancer Society in Stockholm (154132, 081141), and the Swedish Breast Cancer Association to T.H. We thank Helen Piwnica-Worms, Gloria Echeverria, Funda Meric-Bernstam, Debu Tripathy, Ken Chen, and Russell Broaddus for useful discussions and Sohrab Shah for assistance with software.

Keywords

breast cancer genomics
cancer aneuploidy
chemotherapy
copy-number evolution
intratumor heterogeneity
single-cell sequencing
therapy resistance
triple-negative breast cancer
tumor evolution

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2018.03.041

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title = "Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing",

abstract = "Triple-negative breast cancer (TNBC) is an aggressive subtype that frequently develops resistance to chemotherapy. An unresolved question is whether resistance is caused by the selection of rare pre-existing clones or alternatively through the acquisition of new genomic aberrations. To investigate this question, we applied single-cell DNA and RNA sequencing in addition to bulk exome sequencing to profile longitudinal samples from 20 TNBC patients during neoadjuvant chemotherapy (NAC). Deep-exome sequencing identified 10 patients in which NAC led to clonal extinction and 10 patients in which clones persisted after treatment. In 8 patients, we performed a more detailed study using single-cell DNA sequencing to analyze 900 cells and single-cell RNA sequencing to analyze 6,862 cells. Our data showed that resistant genotypes were pre-existing and adaptively selected by NAC, while transcriptional profiles were acquired by reprogramming in response to chemotherapy in TNBC patients. Combination of single-cell DNA and RNA sequencing depicts the evolutionary trajectories of chemoresistance in human triple-negative breast cancer at the genomic and transcriptomic level, highlighting the presence of pre-existing genomic alterations and transcriptional reprogramming of resistant signatures.",

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AU - Foukakis, Theodoros

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AB - Triple-negative breast cancer (TNBC) is an aggressive subtype that frequently develops resistance to chemotherapy. An unresolved question is whether resistance is caused by the selection of rare pre-existing clones or alternatively through the acquisition of new genomic aberrations. To investigate this question, we applied single-cell DNA and RNA sequencing in addition to bulk exome sequencing to profile longitudinal samples from 20 TNBC patients during neoadjuvant chemotherapy (NAC). Deep-exome sequencing identified 10 patients in which NAC led to clonal extinction and 10 patients in which clones persisted after treatment. In 8 patients, we performed a more detailed study using single-cell DNA sequencing to analyze 900 cells and single-cell RNA sequencing to analyze 6,862 cells. Our data showed that resistant genotypes were pre-existing and adaptively selected by NAC, while transcriptional profiles were acquired by reprogramming in response to chemotherapy in TNBC patients. Combination of single-cell DNA and RNA sequencing depicts the evolutionary trajectories of chemoresistance in human triple-negative breast cancer at the genomic and transcriptomic level, highlighting the presence of pre-existing genomic alterations and transcriptional reprogramming of resistant signatures.

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Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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