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. Access through your institution Buy or subscribe This

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vasculogenic mimicry. _Am. J. Pathol._ 155, 739–752 (1999). CAS  PubMed  PubMed Central  Google Scholar  Download references 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. AUTHOR INFORMATION Author notes * Jolanta M Topczewska and Lynne-Marie

Postovit: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Program in Developmental Biology, Children's Memorial Research Center, Feinberg School of Medicine

Northwestern University, 2300 Children's Plaza, Box 222, Chicago, 60614, Illinois, USA Jolanta M Topczewska, Anthony Sam & Jacek Topczewski * Program in Cancer Biology and

Epigenomics, Children's Memorial Research Center, Feinberg School of Medicine Northwestern University, 2300 Children's Plaza, Box 222, Chicago, 60614, Illinois, USA Lynne-Marie

Postovit, Naira V Margaryan, Angela R Hess, William W Wheaton & Mary J C Hendrix * Department of Pathology, Loyola University Medical Center, Cardinal Bernardin Cancer Center, 2160 S.

First Avenue, Building 112, Room 301, Maywood, 60153, Illinois, USA Brian J Nickoloff Authors * Jolanta M Topczewska View author publications You can also search for this author inPubMed 

Google Scholar * Lynne-Marie Postovit View author publications You can also search for this author inPubMed Google Scholar * Naira V Margaryan View author publications You can also search

for this author inPubMed Google Scholar * Anthony Sam View author publications You can also search for this author inPubMed Google Scholar * Angela R Hess View author publications You can

also search for this author inPubMed Google Scholar * William W Wheaton View author publications You can also search for this author inPubMed Google Scholar * Brian J Nickoloff View author

publications You can also search for this author inPubMed Google Scholar * Jacek Topczewski View author publications You can also search for this author inPubMed Google Scholar * Mary J C

Hendrix View author publications You can also search for this author inPubMed Google Scholar 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. ETHICS DECLARATIONS COMPETING INTERESTS 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) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 02 February

2005 * Accepted: 21 June 2006 * Published: 30 July 2006 * Issue Date: 01 August 2006 * DOI: https://doi.org/10.1038/nm1448 SHARE THIS ARTICLE Anyone you share the following link with will

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