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 #
5R01AR043369-18
Application #
8624658
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
2014-03-01
Budget End
2015-02-28
Support Year
18
Fiscal Year
2014
Total Cost
$342,200
Indirect Cost
$129,700
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Alves, Cleidson P; Yokoyama, Satoro; Goedert, Lucas et al. (2016) MYO5A gene is a target of MITF in melanocytes. J Invest Dermatol :
Xia, Yun; Li, Ying; Westover, Kenneth D et al. (2016) Inhibition of Cell Proliferation in an NRAS Mutant Melanoma Cell Line by Combining Sorafenib and α-Mangostin. PLoS One 11:e0155217
Wang, Hequn; Osseiran, Sam; Igras, Vivien et al. (2016) In vivo coherent Raman imaging of the melanomagenesis-associated pigment pheomelanin. Sci Rep 6:37986
Merlino, Glenn; Herlyn, Meenhard; Fisher, David E et al. (2016) The state of melanoma: challenges and opportunities. Pigment Cell Melanoma Res 29:404-16
Shen, Che-Hung; Kim, Sun Hye; Trousil, Sebastian et al. (2016) Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma. Nat Med 22:1056-61
Lauss, Martin; Haq, Rizwan; Cirenajwis, Helena et al. (2015) Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation. J Invest Dermatol 135:1820-8
Dadras, Soheil S; Lin, Richard J; Razavi, Gita et al. (2015) A novel role for microphthalmia-associated transcription factor-regulated pigment epithelium-derived factor during melanoma progression. Am J Pathol 185:252-65
Rachmin, Inbal; Amsalem, Eden; Golomb, Eliahu et al. (2015) FHL2 switches MITF from activator to repressor of Erbin expression during cardiac hypertrophy. Int J Cardiol 195:85-94
Lu, Fa-Ke; Basu, Srinjan; Igras, Vivien et al. (2015) Label-free DNA imaging in vivo with stimulated Raman scattering microscopy. Proc Natl Acad Sci U S A 112:11624-9
Lo, Jennifer A; Fisher, David E; Flaherty, Keith T (2015) Prognostic Significance of Cutaneous Adverse Events Associated With Pembrolizumab Therapy. JAMA Oncol 1:1340-1

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