Topczewska et al. reply:
We agree with Dr. Salomon that it will be interesting to further explore the mechanisms by which Nodal regulates melanoma cell behavior. We did not intend to slight his work linking Cripto-1 to tumorigenesis and therefore cited his seminal paper1 highlighting the expression of Nodal in testicular and breast carcinoma cells of epithelial origin. However, our paper is the first to report Nodal in melanoma, a mesenchymally derived tumor that does not undergo epithelial-to-mesenchmyal transition and contains fewer than 20% Cripto-1–positive cells. Thus, we did not wish to suggest the involvement of a Cripto-1–dependent pathway without more compelling evidence. A role for Cripto-1 in melanoma pathogenesis also remains uncertain because during development, Nodal apparently signals in part through stimulation—rather than inhibition—of a Cripto-1–independent bone morphogenetic protein (BMP) pathway2. The intent of our study was to use the zebrafish embryo as a biosensor for metastatic melanoma cells expressing a plastic, stem cell–like phenotype to modulate an embryonic microenvironment, which ultimately revealed Nodal as a mediator of melanoma plasticity and progression. As a corollary to our findings, we agree that it will be interesting to explore the possible role of Cripto-1 in Nodal-mediated tumorigenesis, tumor progression and metastasis.
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Ben-Haim, N. et al. Dev. Cell 11, 313–323 (2006).
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Topczewska, J., Postovit, L., Margaryan, N. et al. Reply to Melanoma pathogenesis and Nodal: a partial picture?. Nat Med 12, 1231 (2006). https://doi.org/10.1038/nm1106-1231b