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Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness

Abstract

Bidirectional cellular communication is integral to both cancer progression and embryological development. In addition, aggressive tumor cells are phenotypically plastic, sharing many properties with embryonic cells. Owing to the similarities between these two types of cells, the developing zebrafish can be used as a biosensor for tumor-derived signals. Using this system, we show that aggressive melanoma cells secrete Nodal (a potent embryonic morphogen) and consequently can induce ectopic formation of the embryonic axis. We further 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. Nodal inhibition also promotes the reversion of melanoma cells toward a melanocytic phenotype. These data suggest that Nodal signaling has a key role in melanoma cell plasticity and tumorigenicity, thereby providing a previously unknown molecular target for regulating tumor progression.

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Figure 1: Melanoma cells induce ectopic body axis formation in zebrafish embryos.
Figure 2: Aggressive C8161-GFP melanoma cells induce ectopic gene expression in zebrafish embryos.
Figure 3: Aggressive melanoma expresses Nodal.
Figure 4: Patterns of Nodal expression in primary and metastatic melanoma lesions.
Figure 5: Nodal signaling promotes an aggressive melanoma phenotype.
Figure 6: Nodal inhibition abrogates melanoma tumorigenicity.

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Acknowledgements

We acknowledge discussions with D. Constam and the input of L. Lee, E. Seftor and R. Seftor. This work was supported in part by US National Institutes of Health (NIH) grants (CA59702 and CA80318), an Illinois Regenerative Medicine Institute grant and a Charlotte Geyer Foundation grant to M.J.C.H.; an Excellence in Academic Medicine grant (FY05EAM) to J.M.T.; Mazza Foundation grants to J.M.T. and M.J.C.H.; NIH grants (CA59327 and CA27502) to B.J.N.; and a Canadian Institutes of Health Research postdoctoral fellowship to L.M.P.

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Authors and Affiliations

Authors

Contributions

J.M.T. carried out the transplantations and RNA injections into zebrafish embryos, whole-mount immunohistochemistry, and confocal and conventional imaging. L.-M.P. did the cell culture, adenoviral transfections, morpholino treatments, cell sorting, clonogenic assays, vasculogenic mimicry assays, mouse studies and western blotting. N.V.M. carried out the immunohistochemical tissue staining in conjunction with B.J.N. and L.-M.P., and did the mouse studies with L.M.P. A.S. carried out fish care and in situ hybridization, and A.R.H. completed the invasion assays. L.-M.P. and J.M.T. wrote the paper, and all authors discussed the results and commented on the manuscript. The project was conceived and orchestrated by M.J.C.H.

Note: Supplementary information is available on the Nature Medicine website.

Corresponding author

Correspondence to Mary J C Hendrix.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Schematic representation of melanoma cell transplantation experiments. (PDF 529 kb)

Supplementary Fig. 2

The overexpression of the lefty1 inhibits secondary axis formation induced by transplanted aggressive C8161 melanoma cells. (PDF 2537 kb)

Supplementary Fig. 3

Patterns of Nodal expression in primary and metastatic cutaneous melanoma and breast carcinoma cell lines. (PDF 433 kb)

Supplementary Fig. 4

Nodal-mediated signaling and gene regulation in melanoma cells. (PDF 103 kb)

Supplementary Fig. 5

TUNEL assay of melanoma cells treated with MONodal or SB431542. (PDF 685 kb)

Supplementary Note (PDF 430 kb)

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Topczewska, J., Postovit, LM., Margaryan, N. et al. Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nat Med 12, 925–932 (2006). https://doi.org/10.1038/nm1448

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