GAB2 in metastatic melanoma

描述(申请人提供)：转移性黑色素瘤是一种侵袭性肿瘤，预后不良。黑色素瘤转移的关键生物学特征是获得迁移能力、生长因子独立性和侵袭潜能。为了确定导致黑色素瘤转移的基因，在一系列转移性黑色素瘤样本中使用BAC阵列CGH和SNP阵列进行全基因组搜索，发现位于11q14.1的GAB2拷贝数增加。GAB2是一种接头分子，能增强多种信号转导通路的激活，如Ras-ERK和PI3K-AKT通路，最近被认为与人类癌症有关；然而，它在黑色素瘤中的作用尚不明确。在我们的初步研究中，我们发现GAB2在黑色素瘤中扩增(~11%)和/或过表达(~47%)。临床相关研究证实，GAB2是一种新的遗传事件，在肢端和粘膜黑色素瘤的子集中扩增，与BRAF、NRAS和KIT中的遗传改变无关。GAB2蛋白的表达与临床黑色素瘤的进展有关，转移性黑色素瘤的表达水平高于原发黑色素瘤(p=0.0137)和黑色素细胞痣(p=0.004)。我们发现，GAB2的过表达增强了黑色素瘤细胞的侵袭性，而GAB2的沉默则减少了黑色素瘤细胞的迁移和侵袭。在缺乏生长因子的情况下，GAB2介导的PI3/PDK1/AKT信号通路的过度激活和PI3K-AKT通路的抑制降低了GAB2介导的肿瘤细胞的迁移和侵袭能力。此外，GAB2还刺激了CDC42-GTP酶的活性，提示它可能是Rho家族GTP酶的调节因子。这些研究表明，GAB2在黑色素瘤转移中的作用尚不明确，并强调了在黑色素瘤中对各种信号转导途径至关重要的GAB2接头分子的重要性。然而，GAB2介导的肿瘤细胞在肿瘤中运动和侵袭的机制尚不清楚。此外，GAB2在黑色素瘤中的作用尚不清楚。在拟议的研究中，我们计划探索GAB2在黑色素瘤中介导的信号转导机制，肿瘤细胞运动和侵袭的机制，以及GAB2在肿瘤进展和转移过程中与其他遗传事件的合作。我们期望确定GAB2在黑色素瘤中的生物学意义，这将为靶向治疗的发展提供基础。公共卫生相关性：GAB2是一种在信号转导途径中具有关键功能的适配蛋白，最近被认为在人类癌症中发挥了作用。这项建议涉及研究GAB2在黑色素瘤中的作用，以提供其靶向是否对治疗有益的基础。

DESCRIPTION (provided by applicant): Metastatic melanoma is an aggressive tumor with a poor prognosis. Critical biologic features of melanoma metastasis are the acquisition of migratory competence, growth factor independence, and invasive potential. In an attempt to identify genes that contribute to melanoma metastasis, a genome-wide search using BAC array CGH and SNP arrays in a series of metastatic melanoma samples identified increased copy numbers of GAB2 located on 11q14.1. GAB2 is an adaptor molecule that potentiates activation of various signal transduction cascades such as RAS-ERK and PI3K-AKT pathways and has recently been implicated in human cancer; however, its role in melanoma is undefined. In our Preliminary Studies, we found GAB2 as either amplified (~11%) and/or overexpressed (~47%) in melanoma. Clinical correlative studies identified GAB2 as a novel genetic event amplified in a subset of acral and mucosal melanomas independent of genetic alterations in BRAF, NRAS, and KIT. GAB2 protein expression correlated with clinical melanoma progression and higher levels of expression were seen in metastatic melanomas compared to primary melanoma (p=0.0137) and melanocytic nevi (p=0.004). We found that overexpression of GAB2 potentiates, whereas silencing of GAB2 reduces, migration and invasion of melanoma cells. GAB2 mediated hyperactivation of PI3/PDK1/AKT signaling in the absence of growth factors, and inhibition of the PI3K-AKT pathway decreased GAB2-mediated tumor cell migration and invasion potential. Furthermore, GAB2 stimulated Cdc42-GTPase activity suggesting its potential as a regulator of Rho family GTPases. These studies demonstrate a previously undefined role for GAB2 in melanoma metastasis and highlight the significance of GAB2 adaptor molecule, critical for various signal transduction pathways, in melanoma. However, the mechanisms of GAB2-mediated tumor cell motility and invasion in cancer are uncharacterized. Moreover, the role of GAB2 in melanoma is unexplored. In the proposed studies, we plan probe mechanistic insights into GAB2-mediated signaling in melanoma, mechanisms of tumor cell motility and invasion, and cooperation of GAB2 with additional genetic events during tumor progression and metastasis. We expect to define the biological significance of GAB2 in melanoma that will provide the basis for development of targeted therapies. PUBLIC HEALTH RELEVANCE: GAB2 is an adapter protein with critical functions in signal transduction pathways and has recently been implicated to play a role in human cancer. This proposal involves studying the contribution of GAB2 in melanoma to provide a basis whether its targeting would be therapeutically beneficial.