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Investigating the Role of BACE2 in Melanocyte Development and Melanoma Progression

研究 BACE2 在黑色素细胞发育和黑色素瘤进展中的作用

基本信息

批准号：
9814738
负责人：
Yan Zhang
金额：
$ 7.97万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-11 至 2019-08-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9814738
关键词：
Address Affect Animals BRAF gene Biological Assay Cell Differentiation process Cell Line Cell Proliferation Cell physiology Cells Cellular Morphology Clinical Treatment Communication Complex Development Embryo Engineering Equilibrium Fishes Gatekeeping Genes Goals Growth Head Heterogeneity Human Human Engineering Hypersensitivity Label Light Malignant Neoplasms Measurement Measures Melanoma Cell Messenger RNA MicroRNAs Modeling Morphology Mus Neoplasm Metastasis Neural Crest Pharmacology Phenotype Pigmentation physiologic function Pigments Play Primary Neoplasm Proteins Research Resolution Role Series Shapes Skin Cancer Skin Neoplasms Stromal Cells Stromal Neoplasm System TP53 gene Tail Therapeutic Time Training Transgenic Model Transgenic Organisms Transplantation Work Zebrafish base career drug sensitivity exosome in vitro Assay in vivo interest knock-down loss of function melanocyte melanoma mutant neoplastic cell novel overexpression personalized medicine pre-doctoral programs small hairpin RNA small molecule transplant model tumor tumor growth tumor heterogeneity tumor microenvironment tumor progression

项目摘要

Project Summary Melanoma is an aggressive skin tumor arising from melanocytes. While it is well documented that cell heterogeneity is prevalent within melanomas with cells varying widely in their degree of pigmentation and cell morphology, clinical treatment of melanoma does not take into account these diverse differentiation states. The mechanisms underlying this phenotypic heterogeneity remain poorly understood, but play important role in drug sensitivity and metastatic capacity. One determinant of phenotypic heterogeneity is the differentiation state of the cell, which can be due to both cell-intrinsic and microenvironmental factors. We have identified a series of genes that play a role in melanoma differentiation state, including the sheddase BACE2. In Aim 1, we demonstrated that human melanomas strongly overexpress BACE2. Using a zebrafish BACE2-/- mutant zebrafish, we showed that BACE2 loss of function leads to enforced differentiation of melanocytes. This suggests that BACE2 is a differentiation gatekeeper that modulates the proper balance between neural crest and melanocyte states. In Aim 2, we will investigate the impact of differentiation on melanoma by manipulating BACE2 level with an emphasis on cell proliferation and metastasis. We will utilize zebrafish transplantation and transgenic models to dissect the step-wise influence of differentiation on primary tumor growth and metastasis. We will then extend this work to human cancer by engineering melanoma cell lines with inducible knockdown of BACE2. These studies will shed light on how BACE2, a gene involved in melanocyte differentiation, affects melanoma growth and metastasis. In my predoctoral training, I will gain a deeper understanding of the tumor heterogeneity resulting from cell intrinsic differentiation status, and this training will prepare me for my transition into postdoctoral research with a focus on how the extrinsic tumor microenvironment shapes tumor heterogeneity.

项目摘要黑色素瘤是一种由黑素细胞引起的侵袭性皮肤肿瘤。虽然有充分的证据表明细胞在黑色素瘤中异质性是普遍，细胞色素沉着程度和细胞由于黑色素瘤的形态不同，因此黑色素瘤的临床治疗没有考虑这些不同的分化状态。的这种表型异质性的机制仍然知之甚少，但在药物敏感性和转移能力。表型异质性的一个决定因素是细胞分化，细胞的状态，这可能是由于细胞内在和微环境因素。我们已经确定了一一系列在黑色素瘤分化状态中起作用的基因，包括脱落酶BACE 2。目标1：证明人黑色素瘤强烈过表达BACE 2。使用斑马鱼BACE 2-/-突变体在斑马鱼中，我们表明BACE 2功能丧失导致黑素细胞的强制分化。这表明BACE 2是一个分化的看门人，调节神经嵴之间的适当平衡，和黑素细胞状态。在目标2中，我们将通过操纵黑色素瘤的分化来研究分化对黑色素瘤的影响。 BACE 2水平，重点是细胞增殖和转移。我们将利用斑马鱼移植，转基因模型来剖析分化对原发性肿瘤生长和转移的逐步影响。然后我们将通过诱导性基因敲低的黑色素瘤细胞系将这项工作扩展到人类癌症在BACE 2这些研究将阐明BACE 2，一个参与黑素细胞分化的基因，黑色素瘤生长和转移。在我的博士前培训中，我将更深入地了解肿瘤的异质性，细胞内在分化状态，这种培训将为我过渡到博士后研究做好准备重点是外源性肿瘤微环境如何塑造肿瘤异质性。