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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043369-21
Application #
9243981
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Tseng, Hung H
Project Start
1996-02-20
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
21
Fiscal Year
2017
Total Cost
$307,980
Indirect Cost
$116,730
Name
Massachusetts General Hospital
Department
Type
Independent Hospitals
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Lin, William M; Fisher, David E (2017) Signaling and Immune Regulation in Melanoma Development and Responses to Therapy. Annu Rev Pathol 12:75-102
Mujahid, Nisma; Liang, Yanke; Murakami, Ryo et al. (2017) A UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin. Cell Rep 19:2177-2184
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
Chen, Xiqun; Chen, Hongxiang; Cai, Waijiao et al. (2017) The melanoma-linked ""redhead"" MC1R influences dopaminergic neuron survival. Ann Neurol 81:395-406
Salma, Nunciada; Song, Jun S; Kawakami, Akinori et al. (2017) Tfe3 and Tfeb Transcriptionally Regulate Peroxisome Proliferator-Activated Receptor ?2 Expression in Adipocytes and Mediate Adiponectin and Glucose Levels in Mice. Mol Cell Biol 37:
Byrne, Elizabeth H; Fisher, David E (2017) Immune and molecular correlates in melanoma treated with immune checkpoint blockade. Cancer 123:2143-2153
Osseiran, Sam; Roider, Elisabeth M; Wang, Hequn et al. (2017) Non-Euclidean phasor analysis for quantification of oxidative stress in ex vivo human skin exposed to sun filters using fluorescence lifetime imaging microscopy. J Biomed Opt 22:1-10
Merlino, Glenn; Herlyn, Meenhard; Fisher, David E et al. (2016) The state of melanoma: challenges and opportunities. Pigment Cell Melanoma Res 29:404-16
Su, Mack Y; Fisher, David E (2016) Immunotherapy in the Precision Medicine Era: Melanoma and Beyond. PLoS Med 13:e1002196

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