Our work is focussed on understanding observed heterogeneity in the molecular biology of melanoma. Starting from analyses of in vitro transcription patterns we developed a new model for disease progression which rests on the capacity for melanoma cells to switch back and forth between two phenotypic states (Hoek et al., 2006). Respectively, these two phenotypes are proliferative and invasive, and we hypothesized that phenotype is determined not by the melanoma cell itself but the microenvironment. We recently demonstrated an in vivo proof-of-principle for phenotype switching in a mouse (Hoek et al., 2008).
Clinical observation has documented the progression from normal melanocyte to metastatic disease, passing through several well defined stages. These include nevi formation, transformation to an in situ primary, progression to a vertical growth phase and then on to distal metastases via the vasculature. For years scientists have sought to describe the molecular changes which precipitate transformation and the subsequent metastatic cascade. These efforts have not yet enabled clinicians to effect a viable therapy.
Metastatic potential is a term which characterizes the capacity for melanoma cells to escape the original tumor and form metastases in distal tissues. Our research has led us to conclude that the activities of cell proliferation and invasion are distinct programs that are determined by microenvironmental influence on signal pathways. In switching between these programs (phenotypes) melanoma cells may also change a great many other factors, including their surface antigen complement. This could explain why experimental immunotherapies have so far failed to show any improvement in patient survival. These ideas were first discussed in a paper we published in 2006 and then tested in 2008 (Hoek et al., 2006; Hoek et al., 2008).