The relentless rise in melanoma incidence provides an opportunity to reevaluate our understanding of its etiology. This proposal represents a longstanding funded project on the MITF transcription factor, whose master regulatory role in melanocyte development was elucidated largely through this NIH-funded research. Among many discoveries are 1) the central role of MITF as a dysregulated oncogene (via amplification or point mutation) and 2) MITF's key role regulating pigmentation, one of the most important predictors of melanoma risk. MITF expression is regulated by MC1R, a receptor whose nonfunctional variants produce the redhair/fairskin phenotype- conferring the highest melanoma risk of any pigment background in man. Here we report a new observation involving BRAF(V600E) melanoma-genesis. In black mice, BRAF(V600E) requires a second """"""""hit"""""""" to produce highly penetrant melanoma (eg PTEN loss). However we observed that in redheads, BRAF(V600E) produced highly penetrant invasive melanomas after brief latency, without providing a second engineered cancer allele. This melanoma-prone behavior of redhead mice occurred without UV exposure. Consequently """"""""fairskin"""""""" melanoma risk in redheads is at least partially independent of UV shielding. Furthermore incorporation of an albino allele (ablating all pigment, but leaving melanocytes otherwise intact) rescued the redhead (""""""""white-redhead"""""""") mice from elevated melanoma risk. Thus the red/blond pigment pathway is a UV-independent melanoma carcinogen, and our animal model provides a robust, tractable system in which to elucidate its mechanistic basis.
In Aim 1 we will examine ROS as potential mediator of pheomelanin carcinogenesis by studying combinations of in vivo, in vitro, deep genome, and mass spec approaches (collaborating with experts in these technologies). We will also study prevention strategies: anti-oxidants and topicals switching skin pigmentation.
Aim 2 investigates a putative melanoma oncogene, PDE4D-IP, amplified in 25% of melanomas, and predicted to disrupt cAMP homeostasis, thereby producing a novel oncogenic mechanism of MITF dysregulation.
Aim 3 examines our discovery of a discrete class of MITF transcriptional targets: REDOX related factors. We believe they function during MITF-induced pigmentation to protect against ROS, including ROS-induced carcinogenesis. Collectively we extend our deep analyses of MITF biology into a translational direction that relates melanocytic homeostasis to melanomagenesis and novel prevention strategies. !

Public Health Relevance

We have discovered an unexpected cancer-causing role of red/blond pigment which is separate from ultraviolet light shielding. Using rigorous genetically defined animal models as well as molecular analyses of a melanoma oncogene called MITF, we will examine previously unrecognized mechanisms of melanoma formation which suggest novel approaches to melanoma prevention. !

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Tseng, Hung H
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Massachusetts General Hospital
United States
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Nguyen, Nhu T; Fisher, David E (2018) MITF and UV responses in skin: From pigmentation to addiction. Pigment Cell Melanoma Res :
Kapp, Friedrich G; Perlin, Julie R; Hagedorn, Elliott J et al. (2018) Protection from UV light is an evolutionarily conserved feature of the haematopoietic niche. Nature 558:445-448
Hejna, Miroslav; Moon, Wooyoung M; Cheng, Jeffrey et al. (2018) Local genomic features predict the distinct and overlapping binding patterns of the bHLH-Zip family oncoproteins MITF and MYC-MAX. Pigment Cell Melanoma Res :
Wein, Marc N; Foretz, Marc; Fisher, David E et al. (2018) Salt-Inducible Kinases: Physiology, Regulation by cAMP, and Therapeutic Potential. Trends Endocrinol Metab 29:723-735
Levy, Carmit; Golan, Tamar; Fisher, David E (2018) miRNA-211 stops the clock. Noncoding RNA Investig 2:
Byrne, Elizabeth H; Fisher, David E (2017) Immune and molecular correlates in melanoma treated with immune checkpoint blockade. Cancer 123:2143-2153
Lin, William M; Fisher, David E (2017) Signaling and Immune Regulation in Melanoma Development and Responses to Therapy. Annu Rev Pathol 12:75-102
Kawakami, Akinori; Fisher, David E (2017) The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology. Lab Invest 97:649-656
Song, J S; London, W B; Hawryluk, E B et al. (2017) Risk of melanocytic nevi and nonmelanoma skin cancer in children after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 52:989-997
Alves, Cleidson P; Yokoyama, Satoru; Goedert, Lucas et al. (2017) MYO5A Gene Is a Target of MITF in Melanocytes. J Invest Dermatol 137:985-989

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