Malignant melanoma cells secrete protein required for embryo formation

A Northwestern University research group has discovered that aggressive melanoma cells secrete Nodal, a protein that is critical to proper embryo formation.

An article describing this research was published today in the advanced online issue of the journal Nature Medicine. The researchers identified the potent and highly unstable embryonic growth factor by injecting aggressive melanoma cells into developing zebrafish embryos, which were used as "biosensors" for tumor cell-derived signals, and were consequently able to induce ectopic (abnormal) embryonic skull and backbone (axes) formation.

"This finding highlights the convergence of tumorigenic and embryonic signaling pathways. From a translational perspective, Nodal signaling provides a novel target for treatment of aggressive cancers such as melanomas," said Mary J. C. Hendrix, the corresponding author, of Children's Memorial Research Center where the discovery was made.

Hendrix is president and scientific director of the Children's Memorial Research Center, professor of pediatrics at Northwestern University Feinberg School of Medicine and a member of the executive committee of The Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Jolanta M. Topczewska and Lynne-Marie Postovit, from Children's Memorial Research Center, co-led the study. Working with Brian Nickoloff of the Cardinal Bernardin Cancer Center at Loyola University Stritch School of Medicine, the investigators found that Nodal protein was present in 60 percent of cutaneous (skin) metastatic melanoma tumors but is absent in normal skin.

They also found that blocking Nodal signaling reduced melanoma cell invasiveness, as well as cancer cell colony formation and tumor-forming ability. Strikingly, nodal inhibition promoted the reversion of these cells toward a normal skin cell type. Like embryonic stem cells, malignant tumor cells similarly receive and send molecular cues during development that promote tumor growth and metastasis, or cancer spread.

The Northwestern study takes advantage of these similarities by using the developing zebrafish to "detect" tumor-derived chemical signals.

In addition, one of the hallmarks of aggressive cancer cells, including malignant melanoma, is their unspecified, "plastic" nature, which is similar to that of embryonic stem cells, expressing genes characteristic of multiple cell types, including endothelial, neural and stem cells.

The Hendrix lab has long hypothesized that the plastic nature of malignant melanoma cells serves as an advantage by enhancing the cells' ability to migrate, invade and metastasize virtually undetected by the immune system.

In this study, the researchers showed that aggressive tumor cells, particularly melanoma, are capable of responding to microenvironmental factors as well as influencing other cells via epigenetic (other than genetic) mechanisms, a quality known as bi-directional cellular communication. Bi-directional cellular communication is integral to both cancer progression and embryological development.

The significance of the research team's finding is profound in that it implies that through secretion of Nodal, aggressive melanoma cells maintain their plasticity and modulate the microenvironment, as exemplified by their ability to direct the formation of zebrafish tissues.

These results also highlight the propensity of tumor cells to communicate bi-directionally and survive within an embryonic microenvironment. Further, the findings illuminate the remarkable plasticity of melanoma cells and the utility of the developing zebrafish as a model for studying the epigenetic modulation of tumor cells.

Melanoma is one of the deadliest forms of cancer. The five-year survival rate for melanoma patients with widespread disease is between 7 percent and 19 percent.

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In addition to Topczewska, Postovit and Nickoloff, researchers on this study included Naira V. Margaryan; Anthony Sam; Angela R. Hess; William W. Wheaton; and Jacek Topczewski, Children's Memorial Research Center, Northwestern University Feinberg School of Medicine.

This study was supported by grants from National Institutes of Health (CA59702 and CA80318); the Illinois Regenerative Medicine Institute; and the Charlotte Geyer Foundation; as well as an Excellence in Academic Medicine grant; Mazza Foundation grants; and a Canadian Institutes for Health Research post-doctoral fellowship awarded to Postovit.

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