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Nevus associated microRNAs as mediators of BRAF-induced growth arrest and biomarkers of melanoma progression

痣相关的 microRNA 作为 BRAF 诱导的生长停滞的介质和黑色素瘤进展的生物标志物

基本信息

批准号：
10684681
负责人：
Robert Laird Judson-Torres
金额：
$ 34.19万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-24 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684681
关键词：
Address Anatomy Area Automobile Driving BRAF gene Benign Biological Assay Biological Models Biology Biopsy CDKN2A gene Cell Cycle Cells Chemoprevention Classification Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cutaneous Melanoma Data Data Set Dermatologist Detection Development Diagnosis Disease Drug Delivery Systems Early Diagnosis Early identification Engineering Environment Event G2/M Arrest Genes Genetic Genetically Engineered Mouse Genomics Goals Growth Histologic Human Human Engineering In Vitro Incidence Interruption Knowledge Lesion MAP Kinase Gene Malignant - descriptor Measurement Mediating Mediator Melanocytic nevus Methods MicroRNAs Modeling Mole the mammal Molecular Molecular Profiling Mutation Neoplasms Nevi and Melanomas Nevus Oncogenes PTEN gene Pathologist Patients Physicians Pilot Projects Positioning Attribute Prevention Prevention strategy Regulation Reporting Reproducibility Role Sampling Signal Transduction Skin Cancer Skin Pigmentation Specificity Survival Rate System Techniques Testing Training Transcript Tumor Suppressor Proteins Validation aurora B kinase benign state cohort detection method diagnostic accuracy differential expression driver mutation early screening high risk high risk population improved in vivo in vivo Model in vivo evaluation inhibitor innovation mRNA Expression melanocyte melanoma melanoma biomarkers melanomagenesis miRNA expression profiling novel novel strategies pre-clinical prevent screening senescence skin lesion transcriptomic profiling tumor tumor progression

项目摘要

Summary A single driver mutation, BRAFV600E, drives half of all melanomas. However, in the majority of cases, acquisition of BRAFV600E instead drives benign tumors, such as melanocytic nevi (the common mole). We seek to decipher the intracellular mechanisms that prevent full transformation, and harness this knowledge to develop candidate early diagnosis and chemoprevention strategies. We have discovered a signature of microRNAs (miRNA) as the most differentially expressed transcripts distinguishing nevi from either normal melanocytes or melanomas. We have reported that expression of these miRNAs classifies biopsied pigmented neoplasms with high diagnostic accuracy. To determine whether knowledge of these miRNAs could aid in the prevention of melanoma: First, we conducted a comprehensive identification and functional screen of the targets of the most predictive miRNA, MIR211-5p. Using freshly isolated and CRISPR engineered human normal, nevus and melanoma melanocytes, we identified inhibition of AURKB expression as a critical mechanism driving both BRAFV600E and MIR211-5p associated growth arrest in vitro. Therefore, in Aim 1, our objective is to assess the roll of the MIR211-5p/AURKB axis in nevus formation and transformation in vivo, and the efficacy of disrupting this axis in melanoma chemoprevention. Second, we generated a non-invasive assay for miRNA screening of pigmented lesions prior to biopsy. In a small pilot study, we found the high accuracy of classification of melanocytic neoplasia was retained. In Aim 2, our objective is to validate the utility of using non-invasive profiling of the miRNA signature to screen pigmented skin lesions. Three advances distinguish our proposal. The first is the reproducibility of our miRNA classifier, currently validated on six independent datasets. Second, our model systems for this disease—engineered primary human melanocytes, nevi, and melanomas, combined with an in vivo system that recapitulates both the genetics and progression of melanoma—puts us in a unique position to control for context-specific effects when studying these critical events. Third, is our development of a non-invasive miRNA profiling assay, a molecular profiling technique that is both non-invasive and lesion-specific. Our team, consisting of experts in both the basic biology of miRNA and melanoma, in vivo models of melanoma, topical drug delivery, and the daily practice of melanoma surveillance, allows us to comprehensively tackle this project. This project has both basic and clinical potential significance. Our studies explore novel explanations for nevus initiation, driven by observations made from clinical lesions. We expect these studies to directly result in an increase in the early detection of melanomas and preclinical validation of a strategy for topical chemoprevention for particularly high-risk individuals and/oror anatomic areas.

总结