Investigating the Role of BACE2 in Melanocyte Development and Melanoma Progression

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，这次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。

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.