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Our Research

The central theme of our laboratory is to understand molecular mechanisms underlying the development and progression of skin cancers. Skin cancer is the most common form of cancer in humans, and it can arise from melanocytes (melanoma) or keratinocytes (basal and squamous cell carcinoma). There is considerable evidence that resistance to apoptosis is a common feature of melanoma and represents a significant obstacle in treating metastatic disease. There is also evidence that dysfunctional apoptosis is involved in the development of ultraviolet (UV)-induced nonmelanoma skin cancers. Our past work has focused on survivin, a newly recognized inhibitor of apoptosis, as a model paradigm to address the role of apoptosis in both melanoma and nonmelanoma skin cancer.

Our research efforts are currently channeled along the following projects:

Role of Survivin in Melanoma Metastasis

We generated mice with melanocyte-specific expression of Survivin (Dct-Survivin) that exhibited enhanced tumor invasion and metastasis, which was unanticipated given that this phenotype was not seen in other mouse tumor models based on Survivin expression in uroepithelium or keratinocytes. While we initially attributed this metastasis predisposition to apoptosis inhibition, since melanoma tumors arising in Dct-Survivin mice exhibited lower rates of spontaneous apoptosis, our finding of the limited capacity of Survivin to protect melanocytes against anoikis (form of apoptosis induced by detachment from the extracellular matrix) led us to consider other possibilities. Indeed, we have found in preliminary studies that expression of Survivin in human melanocytes and melanoma cells enhances both cell migration and invasion, and that Survivin is required for constitutive motility of melanoma cells. This requirement was observed under conditions where proliferation was blocked and cells were not undergoing apoptosis. We have also shown that the Survivin-enhanced migratory effect in melanoma cells is dependent on Akt activation and consequent upregulation of alpha-5 integrin that occurs following Survivin overexpression. We thus hypothesize that expression of Survivin may promote melanoma metastasis through mechanisms other than regulation of apoptosis and mitosis. We plan to investigate the Survivin-Akt-alpha5 integrin pathway in animal models of melanoma.

mouse tumor

UV-induced melanoma
tumor on a mouse

Role of p16 in Regulating Oxidative Stress

Another focus of the lab is on the role of oxidative stress in melanoma development and targeting this pathway for melanoma chemoprevention. We have shown that the oral antioxidant N-acetylcysteine (NAC) can delay onset of UV-induced melanoma in mice, and more recently that the p16 tumor suppressor, which is frequently mutated or deleted in melanomas, acts to regulate intracellular oxidative stress. This represents a novel function of p16 that is independent of its regulation of the retinoblastoma (Rb) pathway and the cell cycle. We will use an in vivo model to test various p16 mutants inherited in patients with melanoma predisposition and those found in human tumors for loss of this oxidative regulatory activity.

mels

Human melanocytes
growing in tissue culture

Targeting Oxidative Stress Pathways in Nevi

We have been studying oxidative responses in melanocytes, and using antioxidants like NAC to modulate UV-induced oxidative damage in these cells and human nevi (moles). Our preliminary studies in patients with numerous nevi showed that NAC could be safely taken orally by patients which modulated the oxidative state of their nevi. Ultimately we hope to perform a clinical trial in patients at increased risk for melanoma, to see if we can protect their nevi from UV-induced oxidative stress/damage by giving NAC prior to UV exposure.

nevi

Numerous nevi on a patient

Clinical Research: Early Melanoma Detection

At Huntsman Cancer Institute in the Mole Mapping Clinic, we provide photographic monitoring for patients with nevi who are at increased risk for melanoma. We have studied the role of photography in decision-making and early diagnosis of melanoma.

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Melanoma lesion on a patient