Honors Theses


John Letterio, MD



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Honors Thesis


While survival rates for localized melanoma are above 98%, metastatic melanoma proves to be an extraordinarily dreadful disease because of its notoriously poor prognosis resulting in less than 15% survival within 5 years. This is due to the fact that the disease is highly resistant to standard cancer therapies. With approximately 40% of melanoma patients progressing to brain metastasis, a greater understanding of the pathways mediating melanoma cell invasion into the brain must be achieved. In this study, a potentially key target often deregulated in melanoma and other cancers, Cyclin- Dependent Kinase 5 (CDK5), will be interrogated for its implications in metastatic melanoma cell invasion into the brain. Despite the observed deregulation of CDK5 in various cancers as well as human metastatic melanoma cell lines, there is currently minimal effort in defining its role in brain metastatic melanoma. This study approaches this problem in an innovative way by exploring Neurotrophin Receptors (NTR) signaling pathways involving CDK5. Specifically, activated Neurotrophin Receptors induce EGR- 1, thus transcribing p35 and activating its obligate partner CDK5. Considering CDK5 is implicated in a variety of cellular processes such as survival and invasion, this pathway supports our central hypotheses that activation of CDK5 through Neurotrophin (NT) signaling is vital in melanoma cell invasion into the brain. In order to test this hypotheses, a transwell invasion assay utilizing human melanoma cells was used in order to mimic melanoma metastasis into a brain micro-environment in vitro. In order to implicate CDK5 in this study, neurotrophin induced invasion of human metastatic melanoma cells with wild-type expression of CDK5 were compared to cells with drug inhibited CDK5 as well as lentivirally transduced CDK5 knockout cells. Upon NT stimulation, metastatic melanoma cells containing active CDK5/p35 demonstrated a higher propensity to invade into the brain micro-environment. Moreover, simultaneous stimulation of metastatic melanoma cells by multiple members of the neurotrophin family were shown to synergistically enhance invasion ability into a brain micro-environment when compared to stimulation by a single type of neurotrophin.

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Biology, undergraduate research