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

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

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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由黑色素细胞引起的侵袭性皮肤肿瘤。虽然有充分的记录是细胞异质性在黑色素瘤中普遍存在，细胞的色素沉着程度差异很大形态学，黑色素瘤的临床治疗没有考虑到这些不同的分化状态。这这种表型异质性为基础的机制仍然鲜为人知，但在药物敏感性和转移能力。表型异质性的决定因素是分化细胞的状态，这可能是由于细胞内部和微环境因素引起的。我们已经确定了在包括Sheddase Bace2在内的黑色素瘤分化状态中发挥作用的一系列基因。在AIM 1中，我们证明人黑色素瘤强烈表达Bace2。使用斑马鱼Bace2 - / - 突变体斑马鱼，我们表明BACE2功能的丧失导致强化黑色素细胞的分化。这表明BACE2是一个分化的看门人，可调节神经rest之间的适当平衡和黑素细胞状态。在AIM 2中，我们将通过操纵分化对黑色素瘤的影响 Bace2水平，重点是细胞增殖和转移。我们将利用斑马鱼移植和转基因模型剖析分化对原发性肿瘤生长和转移的逐步影响。然后，我们将通过与可诱导型敲低的工程黑色素瘤细胞系一起扩展到人类癌症 Bace2。这些研究将阐明BACE2如何影响黑素细胞分化的基因，会影响黑色素瘤生长和转移。在我的培训前训练中，我将对肿瘤异质性有更深入的了解细胞内在的分化状态，这种培训将使我为过渡到博士后研究做好准备侧重于外部肿瘤微环境如何塑造肿瘤异质性。