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Influence of Melanocyte Differentiation State on Melanoma Susceptibility

黑色素细胞分化状态对黑色素瘤易感性的影响

基本信息

批准号：
10204710
负责人：
Miriam Doepner
金额：
$ 4.6万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2023-07-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204710
关键词：
3-Dimensional AKT Signaling Pathway African American Architecture Binding Biology Caucasians Cells Cessation of life Clinical Coupled Data Disease Doctor of Philosophy Dopa Dopamine Dose Exhibits Exposure to G alpha q Protein G-Protein-Coupled Receptors Glutamate Receptor Growth Human Human Genome Immunotherapy Incidence Intrinsic factor Light MAP Kinase Gene Malignant - descriptor Mediating Medical Melanins Melanoma Cell Metastatic Melanoma Modeling Modernization Monophenol Monooxygenase Mus North Carolina Oncogenes PI3K/AKT Pathway interactions Patients Pharmacology Phenotype Phenylthiourea Pigments Predisposition Prevention Production Proto-Oncogene Proteins c-myc Radiation induced damage Risk Role SCID Mice Signal Transduction Signaling Molecule Site Skin Skin Cancer Skin Pigmentation Testing The Sun Time Tissues Translating Ultraviolet Rays United States Universities Work Xenograft procedure eumelanin experimental study genetic approach in vivo in vivo Model inhibitor/antagonist melanocyte melanoma metabotropic glutamate receptor 5 new therapeutic target novel therapeutics protective factors receptor stem cell biomarkers targeted treatment transcriptome sequencing tumor initiation tumor progression tumorigenesis tumorigenic ultraviolet ultraviolet damage

项目摘要

Project Summary: Melanoma is the most lethal skin cancer with over 90,000 new cases in United States each year. The risk of developing melanoma is substantially greater for people with lightly pigmented skin (1:38 in the US) than those with darkly pigmented skin (1:1000 in the US). Although this discrepancy is generally attributed to the physical UV shielding effect of melanin pigment, the sun protective factor (SPF) of melanin is only 2-3, which seems insufficient to explain the 40-fold difference of melanoma incidence in darkly and lightly pigmented skin. Our preliminary data show that primary human melanocytes (MCs) from lightly pigmented skin produce less melanin relative to primary MCs from dark skin, and this is associated with a decreased MC differentiation state and increased proliferative capacity. Additionally, the proliferation and differentiation differences between light and dark MCs persist upon transformation of primary MCs with medically relevant melanoma drivers (BRAFV600E, CDK4R24C, P53R248W, and hTERT). To test if these differences translated into different melanoma phenotypes in vivo, I engineered architecturally faithful 3-D human skin and orthotopically xenografted the tissue on SCID mice. My preliminary data show that transformed light MCs form early melanomas, whereas transformed dark MCs do not. This observation led us to question whether this stark difference was mediated by melanin synthesis itself, or by intermediates of melanin synthesis, such as dihydroxyphenylalanine (DOPA). We found that darkly pigmented MCs contain approximately 300% more DOPA, as compared to light MCs. Previous work along with my preliminary data show that DOPA serves as a signaling molecule and inhibits proliferation. Specifically, I found that exogenously supplied DOPA induces melanin synthesis in light MCs and melanoma cells, but has no effect on primary dark MC, which likely contain saturating levels of endogenously produced DOPA. The mechanism(s) of the DOPA anti-proliferative effect are currently unknown, but my preliminary data show that DOPA inhibits canonical Gq GPCR pathways leading to a decrease in MAPK and PI3K/AKT signaling pathways. In a collaborative effort with Dr. Bryan Roth at the University of North Carolina, we conducted a functional screen to test whether DOPA binds to any of the ~320 non-olfactory GPCRs in the human genome. The top hit was the Gq-coupled metabotropic glutamate receptor 5 (GRM5), which is a known melanoma driver. Aim 1 will focus on determining the mechanism of DOPA’s anti-proliferative effect, by specifically focusing on its inhibitory role of GRM5, or other top hits from our GPCR screen. Additionally, I determined that DOPA inhibits growth of medically relevant syngeneic BRaf-driven melanoma in vivo. Aim 2 seeks to further understand the endogenous and exogenous roles of DOPA in melanoma inhibition in medically-relevant melanoma models in vivo. Together, these aims will help to define the underexplored melanoma pathobiology responsible for increased melanoma in lightly pigmented people, and may identify new therapeutic targets to benefit melanoma patients.

项目总结: