Melanoma is a common and potentially life-threatening form of skin cancer that arises from melanocytes in the epidermis. Melanoma incidence continues to increase rapidly in the U.S., and our state of Utah leads the nation in both melanoma incidence and mortality. Despite recent therapeutic advances, most patients with metastatic disease will ultimately succumb to it. Melanoma development is initiated by mutations in key genes (i.e. BRaf, NRas), and promoted by ultraviolet (UV) radiation that induces inflammation and cytokine production in the tumor microenvironment.
Known risk factors for melanoma include personal or family history, fair skin, red hair, and numerous or atypical melanocytic nevi (or moles). Although melanoma may arise directly from isolated melanocytes, up to half of melanomas develop from nevi. While melanoma risk is largely genetically determined, exposure to UV radiation in sunlight is the major environmental risk factor.
Our work is focused on understanding how particular genes promote (or inhibit) the development and progression of melanoma, and to use this knowledge to develop novel strategies for reducing melanoma risk in susceptible individuals. Current and past research projects are summarized below.
Regulatory Mechanisms of Apoptosis in Melanoma
Our initial work on the apoptosis inhibitor Survivin elucidated the cellular pathways triggered by loss of Survivin function in melanoma cells, and characterized its function when expressed in normal skin cells and in tumor cells in the context of skin cancer.
- Grossman D, Kim PJ, Schechner JS, Altieri DC (2001): Inhibition of melanoma tumor growth in vivo by survivin targeting. Proc Natl Acad Sci USA 98:635-640. PMCID: PMC14640
- Grossman D, Kim PJ, Blanc-Brude OP, Brash DE, Tognin S, Marchisio PC, Altieri DC (2001): Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53. J Clin Invest 108:991-999. PMCID: PMC200956
- Allen SM, Florell SR, Hanks AN, Alexander A, Diedrich MJ, Altieri DC, Grossman D (2003): Survivin expression in mouse skin prevents papilloma regression and promotes chemical-induced tumor progression. Cancer Res 63:567-572.
- Liu T, Biddle D, Hanks AN, Brouha B, Yan H, Lee RM, Leachman SA, Grossman D (2006): Activation of dual apoptotic pathways in human melanocytes and protection by Survivin. J Invest Dermatol 126:2247-2256. PMCID: PMC2292407
Role of Survivin in Melanoma Metastasis
Our subsequent work on Survivin focused on its role in promotion of cellular migration and melanoma metastasis. We identified a novel pathway by which Survivin upregulates expression of 5 integrin, which is required for Survivin-enhanced melanoma cell migration and metastasis. I served as the primary investigator in all of these studies.
- Thomas J, Liu T, Cotter MA, Florell SR, Robinette K, Hanks AN, Grossman D (2007): Melanocyte expression of Survivin promotes development and metastasis of UV-induced melanoma in HGF transgenic mice. Cancer Res 67:5172-5178. PMCID: PMC2292453
- McKenzie J, Liu T, Goodson AG, Grossman D (2010): Survivin enhances motility of melanoma cells by supporting Akt activation and α5 integrin upregulation. Cancer Res 70:7927-7937. PMCID: PMC2955769
- McKenzie J, Liu T, Jung JY, Jones BB, Ekiz HA, Welm AL, Grossman D (2013): Survivin promotion of melanoma metastasis requires upregulation of α5 integrin. Carcinogenesis 34:2137-2144. PMCID: PMC3765044
Genetic Mechanisms of Melanoma Predisposition
A second area of our basic research has uncovered a novel role for the CDKN2A (p16) tumor-suppressor in regulating oxidative stress. I served as the primary investigator in all of these studies.
- Jenkins NC, Liu T, Cassidy P, Leachman SA, Boucher KM, Goodson AG, Samadashwily G, Grossman D (2011): The p16INK4A tumor suppressor regulates cellular oxidative stress. Oncogene 30:265-274. PMCID: PMC3003740
- Jenkins NC, Jung J, Liu T, Wilde M, Holmen SL, Grossman D (2013): Familial melanoma-associated mutations in p16 uncouple its tumor suppressor functions. J Invest Dermatol 133:1043-1051. PMCID: PMC3594444
- Tyagi E, Liu B, Li C, Liu T, Rutter J, Grossman D (2017): Loss of p16INK4A stimulates aberrant mitochondrial biogenesis through a CDK4/Rb-independent pathway. Oncotarget 8:55848-55862. (Priority Research Paper)
Oxidative Stress in Melanoma
Another interest in my laboratory has been in the area of oxidative stress and its role in melanoma development. We showed that oxidative stress plays a critical role in UV-induced melanoma in mice, and that melanoma in this model could be delayed by oral ingestion of the potent antioxidant N-acetylcysteine (NAC). We subsequently completed a phase I study in a group of my patients at risk for melanoma, showing that NAC is safe, well-tolerated, and its metabolites could be detected in melanocytic nevi (moles). This work laid the foundation for a recently-completed melanoma chemoprevention trial using NAC. I served as the primary investigator in all of these studies.
- Cotter MA, Thomas J, Cassidy P, Robinette K, Jenkins N, Florell SR, Leachman SA, Samlowski WE, Grossman D (2007): N-acetylcysteine protects melanocytes against oxidative stress/damage and delays onset of UV-induced melanoma in mice. Clin Cancer Res 13:5952-5958. PMCID: PMC2409148
- Goodson AG, Cotter MA, Cassidy P, Wade M, Florell SR, Liu T, Boucher KM, Grossman D (2009): Use of oral N-acetylcysteine for protection of melanocytic nevi against UV-induced oxidative stress: towards a novel paradigm for melanoma chemoprevention. Clin Cancer Res 15:7434-7440. PMCID: PMC2787788
- Cassidy P, Liu T, Florell SR, Honeggar M, Leachman SA, Boucher KM, Grossman D (2017): A phase II randomized placebo-controlled trial of oral N-acetylcysteine for protection of melanocytic nevi against UV-induced oxidative stress in vivo. Cancer Prev Res 10:36–44. PMCID: PMC5219848
Early melanoma detection
Finally, I am a nationally recognized expert in melanoma detection and the use of photography in monitoring high-risk patients.
- Goodson AG, Florell SR, Hyde M, Bowen GM, Grossman D (2010): Comparative analysis of total body vs. dermatoscopic photographic monitoring of nevi in similar patient populations at risk for cutaneous melanoma. Dermatol Surg 36:1087-1098. PMCID: PMC3025478
- Malvehy J, Hauschild A, Curiel-Lewandrowski C, Mohr P, Hofmann-Wellenhof R, Motley R, Berking C, Grossman D, Paoli J, Loquai C, Olah J, Reinhold U, Wenger H, Dirschka T, Davis S, Henderson C, Rabinovitz H, Welzel J, Schadendorf D, Birgersson U (2014): Clinical performance of the Nevisense system in cutaneous melanoma detection: an international, multi-centre, prospective and blinded clinical trial. Br J Dermatol 171:1099-1107.
- King AJ, Carcioppolo N, Grossman D, John KK, Jensen JD (2015): A randomized test of printed educational materials about melanoma detection: Varying skin self-examination technique and visual image dose. Health Education J 74:732-742.
- Truong A, Strazzulla L, March J, Boucher KM, Nelson KC, Kim CC, Grossman D (2016): Reduction in nevus biopsy rates in patients monitored by total body photography. J Am Acad Dermatol 75:135-143.
We’ve collaborated with the following Huntsman Cancer Institute labs: