Tumour heterogeneity is the cause for intra-tumour signalling, which can contribute to cancer progression and impact on the efficacy of cancer drugs. With increasing evidence of genetic and phenotypic heterogeneity within tumours, signalling between individual cancer-cell subpopulations is therefore an important factor in cancer biology and therapy. We have identified the lineage specific transcription factor MITF as an important player in phenotypic heterogeneity (MITFhigh and MITFlow cells) crucial for the response to MAP-kinase pathway targeted therapy. Thereby ‘MITF heterogeneity’ can be caused by cell-autonomous mechanisms or by the tumour-microenvironment.
MITF-heterogeneity can also impact on melanoma progression. We analysed the interaction between MITFhigh and MITFlow subpopulations during early steps of melanoma dissemination in a newly established zebrafish xenograft model. Most strikingly, in a heterogeneous setting MITFlow inherently-invasive cells co-invade with subpopulations of MITFhigh poorly-invasive cells, a phenomenon we term ‘co-operative invasion’. During co-operative invasion, the MITFlow invasive cells provide protease activity and deposit extracellular matrix (ECM), and the MITFhigh poorly invasive cells benefit from this heterogeneous situation. On the other hand, the MITFhigh cells modify the mode of invasion of both subpopulations, and as a consequence heterogeneous tumours invade more efficiently. Importantly, we did not observe ‘clonal selection’ for a particular melanoma cell subpopulation or changes in the MITF driven ‘EMT’ expression programme during co-operative invasion. Thus, our data identify co-operativite behaviour between melanoma cell subpopulations as a crucial mechanism that drives melanoma progression and allows preserving heterogeneity without the need for clonal selection or nuclear reprogramming.
1. Smith, M.P., Sanchez-Laorden, B., O’Brien, K., Dhomen, N., Brunton, H., Ferguson, J., Young, H., Flaherty, K.T., Frederick, D.T., Cooper, Z.A., Wargo, J.A., Marais, R. and Wellbrock, C. (2014) The immune-microenvironment confers resistance to MAP kinase pathway inhibitors through macrophage-derived TNFa, Cancer Discovery 4, 1214-29.
2. Chapman, A., Fernandez del Ama, L., Wellbrock, C*. and Hurlstone, A*. (2014) Heterogeneous tumour-subpopulations co-operate to drive invasion, Cell Reports 8, 688-95.