Reprogramming metastatic tumour cells with embryonic microenvironments

Key Points Aggressive tumour cells, such as melanoma, share many characteristics with embryonic progenitors, which contribute to the conundrum of tumour cell plasticity. The challenge is to better understand the aetiology of the plastic, multipotent phenotype and to develop strategies that might include their differentiation and subsequent targeting. A complex and still enigmatic relationship exists between stem cells and their microenvironment that has a crucial role in the determination of cell fate. Current studies identifying the molecular pathways that regulate stem cell plasticity are also examining the epigenetic role of the microenvironment. The microenvironment of human embryonic stem cells can epigenetically reprogramme multipotent metastatic melanoma cells to assume a melanocyte-like phenotype. In addition, the 'reverted' melanoma cells show significantly reduced invasive and tumorigenic ability. The embryonic neural crest microenvironment of the chick provides an attractive model system to explore melanoma tumour cell reprogramming. Human metastatic melanoma cells transplanted into the chick embryonic microenvironment did not form tumours, and a subset of these tumour cells were reprogrammed to a neural crest cell-like phenotype. The melanoma cells also followed neural crest migratory pathways and populated host peripheral structures in a programmed manner. Recent findings using the embryonic zebrafish have illuminated a convergence in the molecular messengers that metastatic tumour and normal stem cells implement during their respective bi-directional communication with the microenvironment, leading to the identification of Nodal. The inhibition of Nodal signalling reduces melanoma cell invasiveness, colony formation and tumorigenicity. Nodal inhibition also promotes the reversion of melanoma cells towards a melanocytic phenotype concomitant with loss of the plastic phenotype. Nodal may represent a new diagnostic marker for disease progression and a novel target for the treatment of aggressive cancers. Additional strategic targets contributing to the Nodal signalling pathway, including SMAD2 and SMAD3, cripto and the activin-like-kinase (ALK) receptor complex, are worth further consideration for inhibiting the plastic tumour cell phenotype. The discovery of key signalling pathways that underlie the commonality of plasticity of embryonic stem cells and multipotent tumour cells will probably result in new therapeutic strategies to suppress the m