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Douglas Grossman

Associate Professor of Oncological Sciences and of Dermatology

B.S. Duke University

Ph.D. Baylor College of Medicine

M.D. Baylor College of Medicine

Research

References

doug.grossman@hci.utah.edu

Doug Grossman's Lab Page

Doug Grossman's PubMed Literature Search

Research

The central theme of my laboratory is understanding molecular mechanisms underlying the development and progression of skin cancers. Skin cancer is the most common form of cancer in humans, and can arise from melanocytes or moles (melanoma) or keratinocytes (basal and squamous cell carcinoma, i.e. non-melanoma skin cancer). There is considerable evidence that resistance to apoptosis (or dysfunctional apoptosis) is a common feature of both melanoma and non-melanoma skin cancers and represents a significant obstacle in treating metastatic disease.

Recent work:

Our initial work has focused on Survivin, an inhibitor of apoptosis, as a model paradigm to address the role of apoptosis in both melanoma and nonmelanoma skin cancer. Initial studies using a transgenic mouse with keratinocyte expression of Survivin revealed that while tumor regression was averted and conversion to carcinoma was enhanced, there was a paradoxical reduction in tumor formation. We have shown that apoptosis is required initially in this model to create space for p53-mutant keratinocyte clones to expand into, that if Survivin is expressed too early, the transition from small to large clones is impaired. Knockdown of p53 induces Survivin expression in keratinocytes, thus UV-induced p53 mutation upregulates Survivin and impairs apoptosis. We have also defined the role of p53 in regulating Survivin in melanocytes. We prepared a transgenic mouse with constitutive expression of Survivin in melanocytes, which exhibits increased susceptibility to UV-induced melanoma and metastasis. We have also become interested in the role of UV-induced oxidative stress and damage in the development of melanoma, and have shown that the antioxidant N-acetylcysteine (NAC) can delay the onset of melanoma in the mouse.

Ongoing projects:

1. Molecular dissection of Survivin function. Using a high throughput screen based on yeast 2-hybrid strategy, we have identified several potential interacting candidate proteins in melanoma cells. We are in the process of validating these interactions by co-immunoprecipitation and assessing effects of knocking down particular candidates with respect to Survivin function.

2. Role of Survivin in melanoma metastasis. In mice with melanocyte-specific expression of Survivin, we observed not only increased UV-induced melanoma development but also metastasis. To understand the mechanisms through which Survivin may promote metastasis, we are screening genes that may be downstream of Survivin and play a non-apoptotic role in metastasis. We will initially be using in vitro assays, but ultimately will validate particular pathways using the in vivo model.

3. Role of p16 and oxidative stress in melanoma. The p16 (CDKN2A) gene is frequently mutated in families with melanoma predisposition, and suppressed by methylation or deleted in melanoma tumors. We are studying its function in normal melanocytes, and its role in melanocyte oxidative responses to UV radiation in vitro and in vivo.

4. Use of NAC for melanoma chemoprevention. We are interested in developing NAC as an oral preventive agent for patients at risk for melanoma. There is an ongoing trial using NAC in patients with atypical nevi as a method to protect these lesions (and normal melanocytes in their skin) from UV-induced oxidative damage.

5. Markers of melanocyte senescence. It has been postulated that melanoma represents failure (or escape) of senescence in melanocytes. The conventional marker of senescence has been pH6 beta-galactosidase staining, but we have shown that melanocytic nevi (moles) do not express pH6 beta-galactosidase activity in vivo. Since this activity reflects lysosomal expansion rather than senescence per se, better markers are needed. We are currently using microarray analysis of proliferating and senescent melanocytes to discover new markers that may be more useful in evaluating melanocytic lesions in the clinic.

References