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：
8913507
负责人：
Andrew Eric Aplin
金额：
$ 35.67万
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/8913507
关键词：
Address Adjuvant Adverse effects BRAF gene Bioinformatics Cell Adhesion Molecules Cell Cycle Arrest Cell Cycle Progression Cells ChIP-seq Cutaneous Melanoma Data Dermal Diagnostic Neoplasm Staging Disease Disease Progression Down-Regulation Early Diagnosis Early treatment Equilibrium Event Goals Growth Heterogeneity In Vitro Incidence Interstitial Collagenase Lead Link MAPK3 gene MEKs Malignant - descriptor Malignant Neoplasms Mediator of activation protein Melanoma Cell Modeling Monophenol Monooxygenase Mus Mutate Mutation Neoplasm Metastasis Nevus Pathway interactions Patients Plastics Play Progression-Free Survivals Property Protein-Serine-Threonine Kinases Publishing Regulation Resistance Role Sampling Series Signal Transduction Skin Skin Cancer Staging Structure TWIST1 gene Testing Therapeutic Transcript Transcription Factor 3 Transcription Repressor/Corepressor Tumor stage Up-Regulation Work cancer type improved in vivo inhibitor/antagonist innovation melanoma mimetics mortality mouse model mutant neoplastic cell pluripotency prevent public health relevance research study 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（由申请人提供）：黑色素瘤是最致命的皮肤癌，我们的目标是了解疾病进展的机制，以便更好地预测和识别黑色素瘤的侵袭性形式，丝氨酸/苏氨酸激酶 BRAF 在 40- 中发生体细胞突变。 60% 的 BRAF 突变是导致 MEK-ERK1/2 信号过度激活以及黑色素瘤生长和侵袭的早期事件。 BRAF 抑制剂现在是转移性突变 V600E BRAF 黑色素瘤的一线治疗方法，它们只能延迟死亡率，并且不会在辅助治疗中使用。因此，我们必须加强对早期黑色素瘤生长和侵袭机制的了解。为了改善预防转移的早期诊断和治疗策略，我们已经确定了黑色素瘤中受突变 BRAF 调节的转录因子 TWIST1 和 FOXD3。为了确定 TWIST1 和 FOXD3 在黑色素瘤进展早期阶段的侵袭和休眠中的作用，我们提出了三个具体目标，以使用 3D 皮肤模拟和突变 BRAF 小鼠模型确定 TWIST1 在原发性黑色素瘤侵袭中的作用，从而从机制上了解 FOXD3。 SOX2（一种与诱导多能性相关的转录因子）的调节，并检查 TWIST1、FOXD3 和 SOX2 之间的相互作用在我们的实验完成后，我们希望能够证明突变型 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级联步骤的机制。