Tumour heterogeneity and co-operative behaviour in melanoma 


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Claudia Wellbrock1
1Manchester Cancer Research Centre, University of Manchester, Manchester, UK

Abstract

Tumour heterogeneity triggers 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.

Melanoma frequently displays heterogeneity with regard to different melanoma cell subpopulations displaying different MITF expression levels. MITF is a transcription factor that controls a melanoma-specific nuclear programme, which is thought to define 'epithelial' or 'mesenchymal'-like melanoma phenotypes. We have previously shown that high MITF expression (MITFhigh) confers cell autonomous resistance to MAP-kinase pathway targeting therapy in melanoma. We have now discovered that in heterogeneous melanomas, MITFhigh therapy-resistant cells could directly protect MITFlow sensitive cells from BRAF inhibitor-induced cell death through intra-tumour signalling.

'MITF-heterogeneity' is also instrumental during melanoma progression. Using a zebrafish xenograft model, we analysed the interaction between MITFhigh and MITFlow subpopulations during early steps of melanoma dissemination. We found that 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.

In summary, our data identified a striking co-operativity between melanoma cell subpopulations that not only impacts on drug response, but also preserves heterogeneity and drives melanoma progression without the need for clonal selection or nuclear reprogramming.