New Insights for Therapeutic Intervention
Re-expression of an Embryonic Signaling Pathway in Melanoma Utilizes Different Receptors than Normal Embryonic Stem Cells
Metastatic melanoma is a highly aggressive skin cancer whose incidence is on the rise at an alarming rate. Research has revealed that metastatic tumor cells share similar signaling pathways with embryonic stem cells to sustain plasticity and growth. However, major regulators of these pathways are often missing in tumor cells, thus allowing uncontrolled tumor growth and spreading to occur.
During early vertebrate development, Nodal, an embryonic growth factor that governs the growth, pattern and position of tissues, is critical for normal maturation. Nodal plays a significant role in maintaining the pluripotency of embryonic stem cells, meaning the ability of stem cells to differentiate into any of the three germ layers that comprise the body.
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 signaling pathway receptors utilized by melanoma cells to propagate Nodal’s effect remain(s) mostly anecdotal and unexplored.
The laboratory of Mary J.C. Hendrix, PhD, President and Director of the Stanley Manne Children’s Research Institute, made the novel discovery that embryonic stem cells and metastatic melanoma cells share a similar repertoire of receptors known as Type I serine/threonine kinase(s), but diverge in their Type II receptor expression. Further testing indicated that metastatic melanoma cells and embryonic stem cells use different receptors for Nodal signal transduction.
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 in cancer.
This work is published in the International Journal of Cancer.
“Nodal-expressing tumor cells don’t respond favorably to conventional therapies, supporting the premise that a combinatorial approach to targeting Nodal subpopulations within tumors, along with a front-line therapy, would constitute a more rational approach for treating aggressive cancer,” said Hendrix, the William G. Swartchild, Jr. Distinguished Research Professor at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Zhila Khalkhali-Ellis, PhD, senior research scientist in the Hendrix laboratory and the lead author said: “Our discoveries are important for advanced stage aggressive melanoma. Given that limited therapeutic options are currently available for this cancer, we have the opportunity to investigate whether the receptors can be modulated so that the signaling molecule can be neutralized to decrease aggressive behavior.” Ellis is a Research Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine; and a member of the Cancer Biology and Epigenomics Program of Stanley Manne Children’s Research Institute, affiliated with Ann & Robert H. Lurie Children’s Hospital of Chicago.
The research was supported by the National Institutes of Health. The research team includes members of the Department of Pediatrics at Northwestern University Feinberg School of Medicine, Chicago, Illinois and the Department of Biochemistry at the University of Texas Health Sciences Center, San Antonio, Texas.
Full citation: Khalkhali-Ellis Z, Kirschmann DA, Seftor EA, Gilgur A, Bodenstine TM, Hinck AP, Hendrix MJC. Divergence(s) in Nodal Signaling Between Aggressive Melanoma and Embryonic Stem Cells. International Journal of Cancer. Available online September 9, 2014.
Stanley Manne Children's Research Institute is the research arm of Ann & Robert H. Lurie Children's Hospital of Chicago, the pediatric teaching hospital for Northwestern University Feinberg School of Medicine. The research institute is also one of the interdisciplinary research centers and institutes of the Feinberg School, where principal investigators who are part of the research institute are full-time faculty members.
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