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、运动和防止细胞凋亡。我们发现，在头颈鳞状细胞癌 (HNSCC) 细胞中，IGF1R 激活会增加血管内皮生长因子 (VEGF) 的合成和分泌，启动自分泌 VEGF:VEGFR2 信号环路。我们的总体假设规定，通过 VEGFR2 的 VEGF 信号传导会导致 HNSCC 致瘤性和侵袭性细胞行为增强。为了有力地支持这一假设，我们鉴定了一组参与 VEGF 刺激激活的细胞运动的蛋白质。这些蛋白质包括人类成丝增强子 1 (HEF1)、皮质素、桩蛋白和粘着斑激酶。重要的是，HEF1（或表达发育下调的 9/NEDD9 的神经前体细胞）已被确定为黑色素瘤和胶质母细胞瘤转移所需的特征蛋白。与此一致的是，我们已经证明 VEGF 刺激的迁移、侵袭和侵袭伪足的形成都依赖于 HEF1 的表达。我们将进一步明确HEF1在HNSCC侵袭行为中的作用，具体目标如下。 AIM 1 的目标是确定 HEF1 介导 VEGF 诱导的 HNSCC 细胞迁移和侵袭的机制。具体来说，我们将使用互补生化技术和定点诱变来定义 HEF1 中响应 VEGFR2 激活而磷酸化的特定酪氨酸残基。我们将进一步定义与这些调节位点结合的效应器，并定义 N 端 SH3 结构域及其相互作用蛋白在入侵中的作用。在 AIM 2 中，我们将定义 VEGF 对侵袭伪足形成的调节以及 HEF1 对此过程的结构和功能贡献。作为该目标的一个子集，我们将检查 HEF1 对侵袭伪足的定位、其 SH3 结构域在此过程中以及在基质金属蛋白酶递送至侵袭伪足中的作用。在 AIM 3 中，我们将检验这一假设：HEF1 表达升高是晚期 HNSCC 肿瘤的预后因素，会导致转移并导致不良预后。还将进行五年生存研究。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。我们还将使用小鼠致癌和异种移植模型来测试 HEF1 对转移的贡献。这些研究将提供重要的证据，证明 HEF1 在与 VEGFR2 串扰的 HNSCC 转移信号下游中的作用。这将导致新策略和治疗药物的开发，旨在减少 HNSCC 中 IGF 和 VEGF 途径的致瘤和转移效应。