Investigator: David Fisher Massachusetts General Hospital (NGH)
Dr. Fisher's Lab at MGH studies cell death/proliferation signals in relation to biological processes including development and pathogenesis. In particular, his Lab particularly studies the cancer of pigment cells (melanoma) and tumors of children, and attempts to understand cell homeostasis with a goal of targeted therapy as well as prevention of melanoma and other human cancers.
Melanoma is the cause of death of roughly 10,000 patients in the United States every year and over 230,000 patients worldwide [1]. Melanoma lesions are often identified as abnormally dark skin regions with irregular pigmented patterns. Their color arises from melanin pigments, of which there are two varieties: eumelanin, a dark and easily identifiable pigment, and pheomelanin, a poorly visible red/blonde pigment seen easier in hair where it is highly concentrated. Across the spectrum of human skin pigmentation, red haired individuals have the palest skin due to their inability to dermally synthesize eumelanin. Redheads also have the highest probability of developing melanoma. A recent landmark study carried out by Dr. David Fisher, Chief of Dermatology at Massachusetts General Hospital, generated a redhead mouse model of melanoma [2] which revealed a UV independent carcinogenic activity of red / pheomelanin pigment - a finding that was recently confirmed in humans [3]. Importantly, the redhead mouse model found that red/blond pigmented melanoma precursor lesions were "invisible" to the naked eye, and could not be detected until the formation of invasive melanoma nodules.
Though the majority of human melanoma lesions are dark and contain brown/black eumelanin, approximately 2-8% of melanoma lesions lack dark pigment, instead appearing red or pink. These so-called amelanotic melanomas are difficult to diagnose, and have been shown to be associated with more advanced depth at the time of clinical detection, as well as higher mortality [4]. Pigment variability within brown/black melanomas can also produce zones lacking dark pigment, which may similarly contain "invisible" pheomelanin - an issue of importance in determining optimal surgical margins. Recent studies in both animal models and human melanomas cells strongly suggest that these amelanotic lesions or foci are in fact pheomelanotic. Taken together, these findings suggest that the detection of pheomelanin is important for the study, diagnosis, and care of melanoma, but there are no clinical instruments capable of visualizing and quantifying melanins on the cellular scale in situ.
Coherent Raman and multiphoton absorption microscopy toolkits have recently gained special consideration for the study and diagnosis of melanoma. In a collaboration between Dr. Fisher's and Dr. Evans' laboratories, coherent anti-Stokes Raman scattering (CARS) was found capable of detecting pheomelanin in cells, mouse models, and human skin. Figure 1 shows that when sum-frequency absorption (SFA) microscopy was additionally utilized, both pheomelanin and eumelanin could be distinguished and quantified. Our approach is to use the portable CARS/SFA system, being developed in Evan's Lab, to investigate both the presence of invisible nevi in the skin of redheaded mouse models as well as their malignant transformation of these nevi. This will be accomplished using redheaded mouse models engineered to contain a CRE-inducible BRAFV600E mutation, the most common mutation found in nevi.
Following topical application of tamoxifen, mouse skin will be monitored to track the appearance of pheomelanin-rich dysplastic cells that serve as precursors to melanoma. Following initial animal studies, next steps will involve a transition to human patients for the identification and tracking of pheomelanotic nevi. The portable CARS system will be used to revisit sites of interest over the course of weeks to follow individual nevi over time. Additional studies will focus on the clinical imaging of amelanotic lesions to identify a set of image-based biomarkers which can be used for clinical diagnostics.
Dr. Fisher (MGH) is investigating the fundamental drivers of melanoma, and believes that the natural pigment pheomelanin is oncogenic. In his effort to translate his findings to the clinic, a turn-key, clinical imaging system will be developed at the LBRC to detect and quantify melanin pigments in patients for both short and long term studies in the biology of melanomagenesis. Wide-field two-photon and second harmonic generation deep tissue imaging technologies may also become complementary tools for in vivo investigation allowing the quantification of cellular metabolism and the extracellular matrix environment.