Mutant BRAF-regulated transcription factors in melanoma progression

黑色素瘤进展中突变的 BRAF 调节转录因子

基本信息

批准号：
9264500
负责人：
Andrew Eric Aplin
金额：
$ 35.69万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-24 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264500
关键词：
Address Adjuvant Adverse effects Alpha Cell BRAF gene Bioinformatics Cell Adhesion Molecules Cell Cycle Arrest Cell Cycle Progression Cell Proliferation Cells ChIP-seq Cutaneous Melanoma Data Dermal Disease Disease Progression Down-Regulation Early Diagnosis Early treatment Equilibrium Event Gene Chips Goals Growth Heterogeneity In Vitro Incidence Interstitial Collagenase Lead Link LoxP-flanked allele MAPK3 gene Malignant - descriptor Malignant Neoplasms Mediator of activation protein Melanoma Cell Modeling Monophenol Monooxygenase Mus Mutate Mutation Neoplasm Metastasis Nevus Pathway interactions Patients Physiological Plasticizers Play Progression-Free Survivals Property Protein-Serine-Threonine Kinases Publishing Regulation Resistance Role Sampling Series Signal Transduction Skin Skin Cancer Structure TWIST1 gene Testing Therapeutic Transcript Transcription Factor 3 Transcription Repressor/Corepressor Tumor stage Up-Regulation actionable mutation cancer type experimental study improved in vivo inhibitor/antagonist innovation melanoma mimetics mortality mouse model mutant neoplastic cell pluripotency prevent public health relevance trait transcription factor treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Melanoma is the deadliest form of skin cancer. We aim to understand mechanisms underlying disease progression in order to better predict and identify aggressive forms of melanomas. The serine/threonine kinase, BRAF, is somatically mutated in 40-60% of melanomas. BRAF mutations are early events that lead to hyper-activation of MEK-ERK1/2 signaling and melanoma growth and invasion. While BRAF inhibitors are now first-line therapies for metastasized mutant V600E BRAF melanomas, they only delay mortality and are not being administered in the adjuvant setting. Thus, we must enhance our understanding of the mechanisms underlying growth and invasion of early-stage melanomas in order to improve early diagnosis and treatment strategies that prevent metastasis. We have identified transcription factors, TWIST1 and FOXD3, which are regulated by mutant BRAF in melanoma. In this proposal, we seek to determine the role of TWIST1 and FOXD3 in invasion and dormancy during the early steps of melanoma progression. We propose three Specific Aims to determine the role of TWIST1 in invasion of primary melanoma using 3D skin mimetic and mutant BRAF mouse models, to mechanistically understand FOXD3 regulation of SOX2 (a transcription factor linked to induced pluripotency), and to examine the interplay between TWIST1, FOXD3 and SOX2 in vivo. At the completion of our experiments, we expect to have demonstrated that the interplay between mutant BRAF-regulated transcription factors controls mechanisms that underlie melanoma plasticity and steps in the metastatic cascade.

描述（适用提供）：黑色素瘤是皮肤癌最致命的形式。我们旨在了解疾病进展的基础机制，以更好地预测和识别侵略性的黑色素瘤。丝氨酸/苏氨酸激酶BRAF在40-60％的黑色素瘤中被体形突变。 BRAF突变是早期事件，导致MEK-ERK1/2信号传导以及黑色素瘤生长和侵袭的过度激活。尽管BRAF抑制剂现在是转移性突变体V600E BRAF黑色素瘤的一线疗法，但它们仅延迟死亡率，并且在调整环境中没有被施用。这是，我们必须增强对早期黑色素瘤生长和入侵的机制的理解，以改善预防转移的早期诊断和治疗策略。我们已经确定了转录因子Twist1和FoxD3，它们受黑色素瘤突变BRAF调控。这项提议，我们试图确定Twist1和FoxD3在黑色素瘤进展早期入侵和休眠中的作用。我们提出了三个特定的目的，以确定Twist1使用3D皮肤模拟物和突变BRAF小鼠模型在侵袭原发性黑色素瘤中的作用，以机械地了解SOX2的FOXD3调节（与诱导的多能性相关的转录因子），并检查Twist1，FoxD3和Sox2 InVivo之间的相互作用。实验完成时，我们希望证明突变体BRAF调节的转录因子之间的相互作用控制着黑色素瘤可塑性和转移性级联的步骤的机制。