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Genetic and transcriptional evolution alters cancer cell line drug response

Author

Listed:
  • Uri Ben-David

    (Broad Institute of Harvard and MIT)

  • Benjamin Siranosian

    (Broad Institute of Harvard and MIT)

  • Gavin Ha

    (Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute)

  • Helen Tang

    (Broad Institute of Harvard and MIT)

  • Yaara Oren

    (Broad Institute of Harvard and MIT
    Harvard Medical School)

  • Kunihiko Hinohara

    (Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute)

  • Craig A. Strathdee

    (Broad Institute of Harvard and MIT)

  • Joshua Dempster

    (Broad Institute of Harvard and MIT)

  • Nicholas J. Lyons

    (Broad Institute of Harvard and MIT)

  • Robert Burns

    (Dana-Farber Cancer Institute)

  • Anwesha Nag

    (Dana-Farber Cancer Institute)

  • Guillaume Kugener

    (Broad Institute of Harvard and MIT)

  • Beth Cimini

    (Broad Institute of Harvard and MIT)

  • Peter Tsvetkov

    (Broad Institute of Harvard and MIT)

  • Yosef E. Maruvka

    (Broad Institute of Harvard and MIT)

  • Ryan O’Rourke

    (Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute)

  • Anthony Garrity

    (Broad Institute of Harvard and MIT)

  • Andrew A. Tubelli

    (Broad Institute of Harvard and MIT)

  • Pratiti Bandopadhayay

    (Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Aviad Tsherniak

    (Broad Institute of Harvard and MIT)

  • Francisca Vazquez

    (Broad Institute of Harvard and MIT)

  • Bang Wong

    (Broad Institute of Harvard and MIT)

  • Chet Birger

    (Broad Institute of Harvard and MIT)

  • Mahmoud Ghandi

    (Broad Institute of Harvard and MIT)

  • Aaron R. Thorner

    (Dana-Farber Cancer Institute)

  • Joshua A. Bittker

    (Broad Institute of Harvard and MIT)

  • Matthew Meyerson

    (Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Gad Getz

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital)

  • Rameen Beroukhim

    (Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Harvard Medical School
    Brigham and Women’s Hospital)

  • Todd R. Golub

    (Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Harvard Medical School
    Howard Hughes Medical Institute)

Abstract

Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Similar results were obtained with multiple strains of 13 additional cell lines. Notably, genetic changes were associated with differential activation of gene expression programs and marked differences in cell morphology and proliferation. Barcoding experiments showed that cell line evolution occurs as a result of positive clonal selection that is highly sensitive to culture conditions. Analyses of single-cell-derived clones demonstrated that continuous instability quickly translates into heterogeneity of the cell line. When the 27 MCF7 strains were tested against 321 anti-cancer compounds, we uncovered considerably different drug responses: at least 75% of compounds that strongly inhibited some strains were completely inactive in others. This study documents the extent, origins and consequences of genetic variation within cell lines, and provides a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.

Suggested Citation

  • Uri Ben-David & Benjamin Siranosian & Gavin Ha & Helen Tang & Yaara Oren & Kunihiko Hinohara & Craig A. Strathdee & Joshua Dempster & Nicholas J. Lyons & Robert Burns & Anwesha Nag & Guillaume Kugener, 2018. "Genetic and transcriptional evolution alters cancer cell line drug response," Nature, Nature, vol. 560(7718), pages 325-330, August.
    • Handle: RePEc:nat:nature:v:560:y:2018:i:7718:d:10.1038_s41586-018-0409-3
    DOI: 10.1038/s41586-018-0409-3
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    Cited by:

    1. Xiaoning Qi & Lianhe Zhao & Chenyu Tian & Yueyue Li & Zhen-Lin Chen & Peipei Huo & Runsheng Chen & Xiaodong Liu & Baoping Wan & Shengyong Yang & Yi Zhao, 2024. "Predicting transcriptional responses to novel chemical perturbations using deep generative model for drug discovery," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. 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.
    3. Jurica Levatić & Marina Salvadores & Francisco Fuster-Tormo & Fran Supek, 2022. "Mutational signatures are markers of drug sensitivity of cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Umberto Perron & Elena Grassi & Aikaterini Chatzipli & Marco Viviani & Emre Karakoc & Lucia Trastulla & Lorenzo M. Brochier & Claudio Isella & Eugenia R. Zanella & Hagen Klett & Ivan Molineris & Julia, 2024. "Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer patient-derived xenografts," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    5. Miles C. Andrews & Junna Oba & Chang-Jiun Wu & Haifeng Zhu & Tatiana Karpinets & Caitlin A. Creasy & Marie-Andrée Forget & Xiaoxing Yu & Xingzhi Song & Xizeng Mao & A. Gordon Robertson & Gabriele Roma, 2022. "Multi-modal molecular programs regulate melanoma cell state," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Maria E. Monberg & Heather Geiger & Jaewon J. Lee & Roshan Sharma & Alexander Semaan & Vincent Bernard & Justin Wong & Fang Wang & Shaoheng Liang & Daniel B. Swartzlander & Bret M. Stephens & Matthew , 2022. "Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Akshaya Ramakrishnan & Aikaterini Symeonidi & Patrick Hanel & Katharina T. Schmid & Maria L. Richter & Michael Schubert & Maria Colomé-Tatché, 2023. "epiAneufinder identifies copy number alterations from single-cell ATAC-seq data," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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