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Cell Rep. 2014 Aug 7;8(3):688-95. doi: 10.1016/j.celrep.2014.06.045. Epub 2014 Jul 24.

Heterogeneous tumor subpopulations cooperate to drive invasion.

Author information

1
Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
2
Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland.
3
Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK. Electronic address: claudia.wellbrock@manchester.ac.uk.
4
Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK. Electronic address: adam.hurlstone@manchester.ac.uk.

Abstract

Clonal selection and transcriptional reprogramming (e.g., epithelial-mesenchymal transition or phenotype switching) are the predominant theories thought to underlie tumor progression. However, a "division of labor" leading to cooperation among tumor-cell subpopulations could be an additional catalyst of progression. Using a zebrafish-melanoma xenograft model, we found that in a heterogeneous setting, inherently invasive cells, which possess protease activity and deposit extracellular matrix (ECM), co-invade with subpopulations of poorly invasive cells, a phenomenon we term "cooperative invasion". Whereas the poorly invasive cells benefit from heterogeneity, the invasive cells switch from protease-independent to an MT1-MMP-dependent mode of invasion. We did not observe changes in expression of the melanoma phenotype determinant MITF during cooperative invasion, thus ruling out the necessity for phenotype switching for invasion. Altogether, our data suggest that cooperation can drive melanoma progression without the need for clonal selection or phenotype switching and can account for the preservation of heterogeneity seen throughout tumor progression.

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PMID:
25066122
PMCID:
PMC4542310
DOI:
10.1016/j.celrep.2014.06.045
[Indexed for MEDLINE]
Free PMC Article
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