The convergence of embryonic & cancer signaling pathways: Role in tumor cell plasticity

Aggressive tumor cells share many characteristics with embryonic progenitors. During development, multipotent precursor cells undergo specific cell fate determination through the autocrine or paracrine delivery of signaling molecules. Similarly, during cancer progression, malignant cells release and receive cues that promote tumor growth and metastasis. In addition, the stem cell‐like plasticity of aggressive tumor cells, particularly melanoma, is suggested by their molecular signature, which defines a dedifferentiated, multipotent plastic phenotype ‐‐ that can respond to microenvironmental factors and influence other cells through epigenetic mechanisms. To address the issue of tumor cell plasticity and to understand the clinical implications of targeting this phenotype, we employed an innovative experimental approach. We used the embryonic microenvironment of the zebrafish as a biosensor for tumor‐derived signals. Using this model, we show that multipotent, aggressive melanoma cells secrete Nodal (a potent embryonic morphogen) and consequently can induce ectopic formation of the embryonic axis. Most noteworthy, we show that Nodal is present in human metastatic tumors, but not in normal skin, and thus may be involved in melanoma pathogenesis. Inhibition of Nodal signaling reduces melanoma cell invasiveness, colony formation, and tumorigenicity. Interestingly, Nodal inhibition also promotes the reversion of melanoma cells toward a melanocytic phenotype concomitant with a diminution of the plastic phenotype. These data suggest that Nodal signaling plays a key role in melanoma cell plasticity and tumorigenicity, thereby providing a previously unknown molecular target for regulating metastatic tumor cell plasticity and progression.