Article | Published:

Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity

Nature volume 514, pages 5458 (02 October 2014) | Download Citation

Abstract

Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumours. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumour phenotypes and the competitive expansion of individual clones. We found that tumour growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumour by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumour collapse. We developed a mathematical modelling framework to identify the rules underlying the generation of intra-tumour clonal heterogeneity. We found that non-cell-autonomous driving of tumour growth, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits.

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Acknowledgements

We thank J. DeGregori, A. Goldman, A. Rozhok, M. Gonen and members of the Polyak and Michor laboratories for their critical reading of this manuscript and discussions. We thank L. Cameron in the DFCI Confocal Microscopy for her technical support. This work was supported by the Dana-Farber Cancer Institute Physical Sciences-Oncology Center (U54CA143798 to F.M.), CDRMP Breast Cancer Research Program W81XWH-09-1-0561 (A.M.), Cellex Foundation (V.A.), Deutsche Akademie der Naturforscher Leopoldina LPDS 2012-12 (P.M.A.) and the Breast Cancer Research Foundation (K.P.).

Author information

Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Andriy Marusyk
    • , Doris P. Tabassum
    • , Vanessa Almendro
    •  & Kornelia Polyak
  2. Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    • Andriy Marusyk
    • , Vanessa Almendro
    •  & Kornelia Polyak
  3. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Andriy Marusyk
    • , Vanessa Almendro
    •  & Kornelia Polyak
  4. BBS Program, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Doris P. Tabassum
    •  & Kornelia Polyak
  5. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Philipp M. Altrock
    •  & Franziska Michor
  6. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA

    • Philipp M. Altrock
    •  & Franziska Michor
  7. Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA

    • Philipp M. Altrock
  8. Harvard Stem Cell Institute and the Broad Institute, Cambridge, Massachusetts 02138, USA

    • Kornelia Polyak

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Contributions

A.M. developed the experimental model, performed xenograft experiments and data analyses. D.P.T. performed immunohistochemical analyses and quantifications, and assisted with animal experiments. P.M.A. performed mathematical modelling and data analyses. V.A. assisted with image acquisition and analyses. K.P. supervised with help from F.M. All authors helped to design the study and write the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kornelia Polyak.

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  1. 1.

    Supplementary Information

    This file contains a Mathematical Supplement, Supplementary References and Supplementary Tables 1-6.

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DOI

https://doi.org/10.1038/nature13556

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