Receptor Crosstalk in HNSCC Metastatic Progression

HNSCC 转移进展中的受体串扰

基本信息

批准号：
8884541
负责人：
STEVEN Alan ROSENZWEIG
金额：
$ 22.46万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884541
关键词：
Alcohols Antibodies Apoptosis Behavior Binding Biochemical Biogenesis Biological Markers Blood capillaries C-terminal Cell Proliferation Cessation of life Data Development Diagnosis Disease Endothelial Cells Enhancers Epidermal Growth Factor Receptor Focal Adhesion Kinase 1 Gelatinase A Gelatinase B Glioblastoma Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Immigration In Vitro Incidence Insulin-Like-Growth Factor I Receptor Lead MMP14 gene Malignant Epithelial Cell Malignant Neoplasms Mass Spectrum Analysis Matrix Metalloproteinases Mediating Mediator of activation protein Metastatic to Mus N-terminal Neoplasm Metastasis Operative Surgical Procedures Pathway interactions Phosphorylation Site Play Process Proteins Receptor Activation Receptor Signaling Recurrence Regulation Research Risk Factors Role SH3 Domains Scaffolding Protein Signal Pathway Signal Transduction Site Site-Directed Mutagenesis Solid Neoplasm South Carolina Specimen Staging System Techniques Testing Therapeutic Agents Tissue Microarray Tobacco Tumor Angiogenesis Tumorigenicity Tyrosine Tyrosine Phosphorylation Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Work Xenograft Model Xenograft procedure angiogenesis autocrine capillary carcinogenesis cell behavior cell growth cell motility cell transformation human EMS1 protein human VEGF protein in vivo laser capture microdissection melanoma migration mouse model neoplastic cell neural precursor cell novel novel strategies novel therapeutics oral carcinogenesis outcome forecast paracrine paxillin prognostic receptor response trafficking tumor tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The insulin-like growth factor 1 receptor (IGF1R) is an essential regulator of cell growth and transformation that promotes tumor cell proliferation, motility and protection from apoptosis. We have shown that in head and neck squamous cell carcinoma (HNSCC) cells IGF1R activation increases vascular endothelial growth factor (VEGF) synthesis and secretion, initiating an autocrine VEGF:VEGFR2 signaling loop. Our overall hypothesis stipulates that VEGF signaling via VEGFR2, leads to enhanced HNSCC tumorigenicity and invasive cell behavior. In strong support of this hypothesis we have identified a cluster of proteins involved in cell motility activated by VEGF stimulation. These proteins include human enhancer of filamentation1 (HEF1), cortactin, paxillin, and focal adhesion kinase. Of significance, HEF1 (or neural precursor cell expressed developmentally down-regulated 9/NEDD9) has been identified as a signature protein required for metastasis in melanoma and glioblastoma. Consistent with this, we have shown that VEGF stimulated migration, invasion and invadopodia formation are all dependent upon HEF1 expression. We will further define the role HEF1 plays in HNSCC invasive behavior in the following aims. The goal of AIM 1 is to define the mechanism through which HEF1 mediates VEGF induced HNSCC cell migration and invasion. Specifically, we will define the specific tyrosine residues in HEF1 that are phosphorylated in response to VEGFR2 activation using complementary biochemical techniques and site-directed mutagenesis. We will further define the effector(s) that bind to these sites of regulation and define the role of the N-terminal SH3 domain and its interacting proteins in invasion. In AIM 2 we will define VEGF regulation of invadopodia formation and the structural and functional contributions of HEF1 to this process. As a subset of this aim we will examine HEF1 localization to invadopodia, the role of its SH3 domain in this process and in matrix metalloproteinase delivery to invadopodia. In AIM 3 we will test the hypothesis that elevated HEF1 expression is prognostic for advanced stage HNSCC tumors in contributing to metastasis and underlying a poor prognosis. Five year survival studies will also be conducted. Human HNSCC tissue arrays and tumor/normal pairs will be examined for HEF1 expression and select activation of signaling pathways. We will also test the contribution of HEF1 to metastasis using mouse carcinogenesis and xenograft models. These studies will provide important evidence demonstrating a role for HEF1 in HNSCC metastatic signaling downstream of crosstalk to VEGFR2. This will lead to the development of novel strategies and therapeutic agents aimed at reducing the tumorigenic and metastatic effects of the IGF and VEGF pathways in HNSCC.

描述（由申请人提供）：胰岛素样生长因子1受体（IGF1R）是细胞生长和转化的重要调节剂，可促进肿瘤细胞增殖，运动和免受凋亡的保护。我们已经表明，在头部和颈部鳞状细胞癌（HNSCC）细胞中，IGF1R激活增加了血管内皮生长因子（VEGF）的合成和分泌，启动自分泌VEGF：VEGFR2信号传导循环。我们的总体假设规定，通过VEGFR2的VEGF信号传导导致HNSCC肿瘤性和侵入性细胞行为的增强。为了强烈支持该假设，我们已经确定了通过VEGF刺激激活的细胞运动的一组蛋白质。这些蛋白质包括人类丝的增强剂1（HEF1），Cortactin，paxillin和局灶性粘附激酶。重要的是，HEF1（或神经前体细胞在发育中表达下调的9/NEDD9）已被确定为黑色素瘤和胶质母细胞瘤中转移所需的特征蛋白。与此相一致，我们已经表明，VEGF刺激迁移，侵袭和侵袭性形成都取决于HEF1的表达。我们将进一步定义HEF1在HNSCC侵入性行为中的作用。目标1的目的是定义HEF1介导VEGF诱导HNSCC细胞迁移和侵袭的机制。具体而言，我们将定义HEF1中的特定酪氨酸残基，这些酪氨酸残基使用互补的生化技术和定位的诱变响应于VEGFR2激活而磷酸化。我们将进一步定义与调节的这些位点结合的效应子，并定义N末端SH3结构域及其相互作用蛋白在侵袭中的作用。在AIM 2中，我们将定义对Invadodia形成的VEGF调节以及HEF1对此过程的结构和功能贡献。作为此目标的一个子集，我们将研究HEF1与Invadopodia的本地化，这是其SH3域在此过程中的作用以及基质金属蛋白酶酶传递至Invadopodia的作用。在AIM 3中，我们将检验以下假设：HEF1表达升高是对高级HNSCC肿瘤的预后，从而有助于转移和预后不良。还将进行五年的生存研究。将检查人类HNSCC组织阵列和肿瘤/正常对的HEF1表达并选择信号通路的激活。我们还将使用小鼠癌变和异种移植模型测试HEF1对转移的贡献。这些研究将提供重要的证据，证明HEF1在串扰向VEGFR2下游的HNSCC转移性信号传导中发挥作用。这将导致旨在减少HNSCC中IGF和VEGF途径的致瘤和转移效应的新型策略和治疗剂的发展。