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

Author

Listed:
  • Mihriban Karaayvaz

    (Massachusetts General Hospital and Harvard Medical School)

  • Simona Cristea

    (Dana-Farber Cancer Institute
    Harvard T. H. Chan School of Public Health
    Harvard University)

  • Shawn M. Gillespie

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Anoop P. Patel

    (Massachusetts General Hospital and Harvard Medical School)

  • Ravindra Mylvaganam

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Christina C. Luo

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Michelle C. Specht

    (Massachusetts General Hospital and Harvard Medical School)

  • Bradley E. Bernstein

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School
    The Broad Institute of Harvard and MIT
    The Ludwig Center at Harvard)

  • Franziska Michor

    (Dana-Farber Cancer Institute
    Harvard T. H. Chan School of Public Health
    Harvard University
    The Broad Institute of Harvard and MIT)

  • Leif W. Ellisen

    (Massachusetts General Hospital and Harvard Medical School)

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.

Suggested Citation

  • Mihriban Karaayvaz & Simona Cristea & Shawn M. Gillespie & Anoop P. Patel & Ravindra Mylvaganam & Christina C. Luo & Michelle C. Specht & Bradley E. Bernstein & Franziska Michor & Leif W. Ellisen, 2018. "Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06052-0
    DOI: 10.1038/s41467-018-06052-0
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    Cited by:

    1. Duy Pham & Xiao Tan & Brad Balderson & Jun Xu & Laura F. Grice & Sohye Yoon & Emily F. Willis & Minh Tran & Pui Yeng Lam & Arti Raghubar & Priyakshi Kalita-de Croft & Sunil Lakhani & Jana Vukovic & Ma, 2023. "Robust mapping of spatiotemporal trajectories and cell–cell interactions in healthy and diseased tissues," Nature Communications, Nature, vol. 14(1), pages 1-25, December.
    2. G. Gambardella & G. Viscido & B. Tumaini & A. Isacchi & R. Bosotti & D. di Bernardo, 2022. "A single-cell analysis of breast cancer cell lines to study tumour heterogeneity and drug response," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Qionghua Zhu & Xin Zhao & Yuanhang Zhang & Yanping Li & Shang Liu & Jingxuan Han & Zhiyuan Sun & Chunqing Wang & Daqi Deng & Shanshan Wang & Yisen Tang & Yaling Huang & Siyuan Jiang & Chi Tian & Xi Ch, 2023. "Single cell multi-omics reveal intra-cell-line heterogeneity across human cancer cell lines," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    4. Brendan F. Miller & Feiyang Huang & Lyla Atta & Arpan Sahoo & Jean Fan, 2022. "Reference-free cell type deconvolution of multi-cellular pixel-resolution spatially resolved transcriptomics data," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    5. Xianke Xiang & Yao He & Zemin Zhang & Xuerui Yang, 2024. "Interrogations of single-cell RNA splicing landscapes with SCASL define new cell identities with physiological relevance," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Brian D. Lehmann & Antonio Colaprico & Tiago C. Silva & Jianjiao Chen & Hanbing An & Yuguang Ban & Hanchen Huang & Lily Wang & Jamaal L. James & Justin M. Balko & Paula I. Gonzalez-Ericsson & Melinda , 2021. "Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    7. Wanying Wu & Jinyang Zhang & Xiaofei Cao & Zhengyi Cai & Fangqing Zhao, 2022. "Exploring the cellular landscape of circular RNAs using full-length single-cell RNA sequencing," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. Tong Liu & Cheng Liu & Meisi Yan & Lei Zhang & Jing Zhang & Min Xiao & Zhigao Li & Xiaofan Wei & Hongquan Zhang, 2022. "Single cell profiling of primary and paired metastatic lymph node tumors in breast cancer patients," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    9. Ji-Yong Sung & Hyun-Tae Shin & Kyung-Ah Sohn & Soo-Yong Shin & Woong-Yang Park & Je-Gun Joung, 2019. "Assessment of intratumoral heterogeneity with mutations and gene expression profiles," PLOS ONE, Public Library of Science, vol. 14(7), pages 1-15, July.
    10. Saba Ahmadi & Pattara Sukprasert & Rahulsimham Vegesna & Sanju Sinha & Fiorella Schischlik & Natalie Artzi & Samir Khuller & Alejandro A. Schäffer & Eytan Ruppin, 2022. "The landscape of receptor-mediated precision cancer combination therapy via a single-cell perspective," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    11. Alma Andersson & Ludvig Larsson & Linnea Stenbeck & Fredrik Salmén & Anna Ehinger & Sunny Z. Wu & Ghamdan Al-Eryani & Daniel Roden & Alex Swarbrick & Åke Borg & Jonas Frisén & Camilla Engblom & Joakim, 2021. "Spatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    12. Ido Nofech-Mozes & David Soave & Philip Awadalla & Sagi Abelson, 2023. "Pan-cancer classification of single cells in the tumour microenvironment," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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