From stem cells to cancer: deciphering the Mitf code


Year:

Session type:

Colin Goding

Ludwig Institute for Cancer Research, Oxford, UK

Abstract

From stem cells to cancer: deciphering the Mitf code

The signalling pathways that drive the program of transcription underpinning the transition from stem cell to differentiation via a transit amplifying population are related to those that are de-regulated in cancer, where cancer stem cells and proliferating progeny may coexist within a tumour. Moreover increasing evidence suggests that the rapid metastasis characteristic of some cancers, especially melanoma, may reflect microenvironment-driven activation of an intrinsic migratory capacity, rather than the acquisition of metastasis-associated genetic mutations.

We recently identified the Microphthalmia-associated transcription factor MITF as a regulator of melanoma proliferation and invasiveness, and provided evidence for a ‘rheostat’ model to resolve the apparent paradox in which MITF can act both to promote and inhibit proliferation. In this model, low levels of MITF yield a non-proliferating but invasive, stem cell-like population, whereas expression of Mitf leads to a program of gene expression compatible with either proliferation or differentiation. Importantly, our results imply that the microenvironment will drive a dynamic and reversible switch, mediated by MITF activity, which will determine the invasive or proliferative potential of individual cells within a tumour. How signal transduction pathways lead to a cascade of post-translational modifications of MITF that control its activity, and how that relates to the transcription programs that determine proliferation vs differentiation will be discussed.