The Phenotype Switch Model

Metastatic potential in melanoma necessitates a combination of invasion to tissues distal from the primary lesion and subsequent proliferation of melanoma cells. Our research has led us to conclude that these behaviours are regulated by separate transcriptional programs and that melanoma cells, responding to changing microenvironments, can switch between these programs.

With help from the laboratories of Meenhard Herlyn and Dirk Schadendorf our lab published a molecular taxonomy of melanoma gene expression and used this to construct a gene regulation model for metastatic potential in melanoma (Hoek et al., 2006). This model describes two phenotypic states of melanoma cell and the active signaling pathways responsible for maintaining their differences. We successfully tested the capacity for melanoma cells to switch between these states in an in vivo model (Hoek et al., 2008).

The phenotypes. A proliferative phenotype is set by Wnt signalling which diverts beta-catenin from ubiquitination to the nucleus where it participates in the regulation of neural crest genes, resulting in cells with weak invasive potential but high proliferation. For the invasive phenotype, TGFbeta-like signalling upregulates factors which drive a positive feedback signal, change the extracellular environment and inhibit Wnt signalling which interrupts expression of neural crest genes - resulting in cells with reduced proliferation but increased invasive potential.		Phenotype switching. Early phase melanoma cells expressing the “proliferative signature” gene set proliferate to form the primary lesion. Following this an unknown signal switch, likely brought about by altered microenvironmental conditions (e.g. hypoxia or inflammation), gives rise to cells with a significantly different “invasive signature” gene set. Invasive signature cells escape and, upon reaching a suitable distal site, revert to the proliferative state and nucleate a new metastasis where the cycle is repeated. Each switch in phenotype (state change) is accompanied by an exchange in expressed gene sets from proliferative to invasive and vice versa.

This model implies that metastases are composed of each of two melanoma cell phenotypes and the transition between cell phenotypes (i.e. that cells of one phenotype can give rise to cells of the other) is dominated by microenvironmental conditions and reversible. If this proves to be an accurate description it offers a possible explanation for why monotherapies and current combinatorial therapies fail to control melanoma (for example, chemotherapy targets fast dividing cells, which represent only half of the above model). The strategy should be to first recognize that melanoma is not one disease but two, and in order to be successful a therapy must take them both into consideration.