Metastatic melanoma is a highly aggressive skin cancer associated with poor clinical outcome. One key feature is the expression of a cellular type resembling embryonic stem cells in its molecular profile. Both stem cells and aggressive melanoma cells participate in bidirectional communication with the microenvironment, which can profoundly influence cell behavior.
During early vertebrate development, the expression of Nodal, an embryonic substance that governs the pattern and position of tissue development, is specifically regulated by a Notch signaling pathway, a receptor protein involved in many instances of choice of cell fate in animal development. Cancer cells can exploit normally dormant embryonic pathways to promote tumor development. The reactivation of Nodal in metastatic melanoma has previously been shown to regulate the aggressive behavior of these tumor cells.
In a study published in the December 15 issue of Cancer Research, the laboratory of Mary J.C. Hendrix hypothesized that cross-talk between the Notch and Nodal pathways can explain the reactivation of Nodal in aggressive metastatic melanoma cells. Here they demonstrate a molecular link between Notch and Nodal signaling in aggressive melanoma, via the activity of a Nodal enhancer element. They show a precise correlation between Notch4 and Nodal expression in multiple aggressive cell lines, but not poorly aggressive cell lines.
Surprisingly, Notch4 is specifically required for expression of Nodal in aggressive cells, and plays a vital role in the balance of cell growth and the regulation of the aggressive phenotype. In addition, Notch4 function in vasculogenic mimicry, a mechanism by which highly aggressive tumor cells can form vessel-like structures to provide nutrients to the tumor, and anchorage independent growth in vitro, is due in part to Notch4 regulation of Nodal. This study identifies an important role for cross-talk between Notch4 and Nodal in metastatic melanoma, and offers a potential molecular target for melanoma therapy.
An image from the study is featured on the cover of the December 15 Cancer Research.
First author Katharine Hardy, PhD, is a post-doctoral fellow in the Hendrix laboratory. Senior author Mary J.C. Hendrix, PhD, is president and scientific director of Children’s Memorial Research Center and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Co-authors Luigi Strizzi, MD, PhD; Naira Margaryan, DVM, PhD; Dawn Kirschmann, PhD; and Elisabeth Seftor, BS; are members of the Hendrix laboratory. Co-author Lynne-Marie Postovit, PhD, is assistant professor in the Department of Anatomy and Cell Biology, The Schulich School of Medicine at the University of Western Ontario, London, Ontario, Canada.
This research was supported by awards from the National Cancer Institute, the Canadian Institutes of Health Research, and Eisenberg Research Scholar Fund.
For more information contact Peggy Murphy at 773.755.6341.
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