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Nature. 2014 Oct 2;514(7520):54-8. doi: 10.1038/nature13556. Epub 2014 Jul 30.

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

Author information

1
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
2
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] BBS Program, Harvard Medical School, Boston, Massachusetts 02115, USA.
3
1] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA [3] Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA.
4
1] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
5
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [4] BBS Program, Harvard Medical School, Boston, Massachusetts 02115, USA [5] Harvard Stem Cell Institute and the Broad Institute, Cambridge, Massachusetts 02138, USA.

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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PMID:
25079331
PMCID:
PMC4184961
DOI:
10.1038/nature13556
[Indexed for MEDLINE]
Free PMC Article
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