Mutant BRAF-regulated transcription factors in melanoma progression

 描述(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侵袭性形式的黑色素瘤。丝氨酸/苏氨酸激酶，BRAF，在40-60%的黑色素瘤中发生体细胞突变。BRAF突变是导致MEK-ERK1/2信号过度激活和黑色素瘤生长和侵袭的早期事件。虽然BRAF抑制剂现在是转移性突变的V600E BRAF黑色素瘤的一线治疗药物，但它们只会推迟死亡率，并且不在辅助环境中使用。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，以便改进早期诊断和治疗策略，防止转移。我们已经确定了在黑色素瘤中受突变的BRAF调控的转录因子Twist1和FOXD3。在这项提案中，我们试图确定Twist1和FOXD3在黑色素瘤进展的早期阶段的侵袭和休眠中的作用。我们提出了三个特定的目标，通过3D皮肤模拟和突变的BRAF小鼠模型来确定Twist1在原发黑色素瘤侵袭中的作用，从机制上理解FOXD3对SOX2(一种与诱导多能性相关的转录因子)的调控，并在体内检查Twist1、FOXD3和SOX2之间的相互作用。在我们的实验完成后，我们希望已经证明，突变的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的基础机制和转移级联反应的步骤。

 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.