Divergence(s) in nodal signaling between aggressive melanoma and embryonic stem cells

• Published in: International journal of cancer Vol. 136; no. 5; pp. E242 - E251
• Main Authors: Khalkhali‐Ellis, Zhila, Kirschmann, Dawn A., Seftor, Elisabeth A., Gilgur, Alina, Bodenstine, Thomas M., Hinck, Andrew P., Hendrix, Mary J.C.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2015
• Subjects: Activin Receptors, Type I - genetics; Activin Receptors, Type I - metabolism; Activin Receptors, Type II - genetics; Activin Receptors, Type II - metabolism; Activins - genetics; Activins - metabolism; Blotting, Western; Cancer; Cells, Cultured; embryonic stem cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Embryos; Humans; Ligands; Medical research; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Metastasis; nodal; Nodal Protein - genetics; Nodal Protein - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Real-Time Polymerase Chain Reaction; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - secondary; Stem cells; TGFβRI; TGFβRII; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; melanoma; TGFβRI; nodal; embryonic stem cells; TGFβRII
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29198

The significant role of the embryonic morphogen Nodal in maintaining the pluripotency of embryonic stem cells is well documented. Interestingly, the recent discovery of Nodal's re‐expression in several aggressive and metastatic cancers has highlighted its critical role in self renewal and maintenance of the stem cell‐like characteristics of tumor cells, such as melanoma. However, the key TGFβ/Nodal signaling component(s) governing Nodal's effects in metastatic melanoma remain mostly unknown. By employing receptor profiling at the mRNA and protein level(s), we made the novel discovery that embryonic stem cells and metastatic melanoma cells share a similar repertoire of Type I serine/threonine kinase receptors, but diverge in their Type II receptor expression. Ligand:receptor crosslinking and native gel binding assays indicate that metastatic melanoma cells employ the heterodimeric TGFβ receptor I/TGFβ receptor II (TGFβRI/TGFβRII) for signal transduction, whereas embryonic stem cells use the Activin receptors I and II (ACTRI/ACTRII). This unexpected receptor usage by tumor cells was tested by: neutralizing antibody to block its function; and transfecting the dominant negative receptor to compete with the endogenous receptor for ligand binding. Furthermore, a direct biological role for TGFβRII was found to underlie vasculogenic mimicry (VM), an endothelial phenotype contributing to vascular perfusion and associated with the functional plasticity of aggressive melanoma. Collectively, these findings reveal the divergence in Nodal signaling between embryonic stem cells and metastatic melanoma that can impact new therapeutic strategies targeting the re‐emergence of embryonic pathways. What's new? Metastatic tumor cells and embryonic stem cells employ similar signaling pathways to maintain plasticity. Both rely, for example, on Nodal, a member of the TGFβ superfamily and a key regulator of cell fate. The present study shows that Nodal signaling in metastatic melanoma cells is carried out through heterodimeric TGFβ receptor I/TGFβ receptor II signal transduction. By contrast, Nodal signaling in embryonic stem cells was governed by Activin receptors I and II. The findings shed light on the divergence of Nodal signaling mechanisms in metastatic tumor cells, with implications for the development of Nodal‐targeting therapeutics.