Signaling Modulators in Epidermal Carcinogenesis

表皮癌变中的信号调节剂

基本信息

批准号：
8539749
负责人：
TODD W RIDKY
金额：
$ 31.21万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-04 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8539749
关键词：
3-Dimensional Adherens Junction Affect Basement membrane Binding Cell physiology Cells Common Neoplasm Complex Data Development Elements Engineering Epidermal Growth Factor Receptor Epidermis Epithelial Family Funding Future Genetic Genetic Engineering Histocompatibility Testing Homeostasis Human IQ motif containing GTPase activating protein 1 In Vitro Individual Laboratories Lead MAP Kinase Gene MAP Kinase Modules Malignant Neoplasms Mediating Medical Mitogen-Activated Protein Kinases Modeling Mus Mutate Mutation Neoplasms Normal tissue morphology Oncogene Proteins Oncogenes Oncogenic Output Pathway interactions Prevention Process Proteins RNA Interference Ras/Raf Role Scaffolding Protein Signal Transduction Site Skin Squamous cell carcinoma Stratification Structure Therapeutic Tissue Engineering Tissue Model Tissue Viability Tissues Toxic effect Visceral angiogenesis base cancer cell carcinogenesis cell motility cell type design human tissue in vivo keratinocyte meetings molecular domain mutant neoplastic new therapeutic target research study scaffold screening therapeutic target tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Activation of the Ras MAP kinase signaling cascade is a central feature common to the majority of human malignancies, making the pathway a potentially high-value target for cancer therapeutics. However, directly targeting canonical elements of this pathway as a therapeutic approach is complicated by systemic toxicities resulting from the fact that Ras MAPK signaling is ubiquitously active in nearly all human tissues, and is required for tissue viability. However, full MAP kinase signaling requires the function of a family of MAPK interacting scaffolding proteins that modulate and orchestrate pathway outputs. Recent data indicates that one of these elements, IQGAP1, which regulates Erk MAPK activity, ?-catenin signaling, cytoskeletal remodeling, and cell motility, is dispensable for normal tissue development and homeostasis, but is required for manifestation of the oncogenic effects of Ras. This proposal aims to define the mechanistic basis for this tumor-specific requirement in a medically-relevant human tissue context. To accomplish this, we will utilize our recently developed three-dimensional human tissue model of genetically-defined invasive epidermal neoplasia generated from primary epidermal keratinocytes expressing tumor-associated active Ras, intact basement membrane, and architecturally faithful native stroma. These models recapitulate hallmark features of epidermal malignancy in vivo including disrupted stratification and differentiation, and invasion through basement membrane into supporting stroma. Engineered tissues will incorporate keratinocytes with RNAi-mediated endogenous IQGAP1 antagonism, combined with expression of IQGAP1 mutants unable to bind specific interacting proteins. These efforts are designed to determine which IQGAP1 functions are most critical for supporting progression to neoplastic invasion. These functional human tissue studies will be important for the design of targeted therapeutics, and are structured to allow for identification of other downstream effectors uniquely required by neoplastic tissue. Second, we will employ additional new genetically-defined human tumor models developed in our laboratory based on expression of different tumor-associated oncogenic driver mutations in primary cells from 12 different tissue types. These engineered neoplasias will be deployed in experiments to define the role of the IQGAP1 scaffold in an array of human tumor types. At the end of the proposed funding period we aim to A) understand the mechanism of IQGAP1 antagonism in epidermal-derived neoplasias as a guide to development of future tumor-selective therapeutics, and B) establish the scope of IQGAP1 necessity in a spectrum of human neoplasias to identify tumor types most likely to be susceptible to inhibition of IQGAP1-mediated processes.

描述（由申请人提供）：RAS MAP激酶信号级联反应的激活是大多数人类恶性肿瘤共有的核心特征，使该途径成为癌症疗法的潜在高价值靶标。然而，将该途径的规范元素直接瞄准作为治疗方法，这是由于ras mapk信号在几乎所有人类组织中无处不在的，并且是组织生存能力所必需的，这是由于全身性毒性而复杂的。但是，完整的MAP激酶信号需要一个MAPK相互作用的脚手架蛋白的功能，该蛋白质调节和编排途径输出。最近的数据表明，这些元素之一是调节ERK MAPK活性的IQGAP1，？ - 蛋白蛋白信号传导，细胞骨架重塑和细胞运动性，对于正常的组织发育和稳态是可分配的，但需要表现出RAS的肿瘤效应的表现。该建议旨在在医学上与人类组织的情况下定义这种肿瘤特异性需求的机理基础。为此，我们将利用我们最近开发的三维人体组织模型的遗传定义的浸润性表皮肿瘤，该模型是由原发性表皮角质形成细胞产生的，这些肿瘤与表达肿瘤相关的活性Ras，完整的基础膜和建筑忠实的天然性骨膜瘤产生。这些模型概括了体内表皮恶性肿瘤的标志性特征，包括破坏分层和分化，以及通过基底膜侵袭到支撑基质中。工程组织将与RNAi介导的内源性IQGAP1拮抗作用结合角质形成细胞，并结合无法结合特定相互作用蛋白的IQGAP1突变体的表达。这些努力旨在确定哪些IQGAP1功能对于支持肿瘤侵袭的发展最为重要。这些功能性的人体组织研究对于靶向治疗剂的设计将很重要，并结构结构允许识别其他下游效应子，由肿瘤组织独特地要求。其次，我们将基于来自12种不同组织类型的原代细胞中不同肿瘤相关的致癌驱动器突变的表达，在实验室开发的其他新的遗传定义的人肿瘤模型。这些工程化的肿瘤将在实验中部署，以定义IQGAP1支架在一系列人类肿瘤类型中的作用。 At the end of the proposed funding period we aim to A) understand the mechanism of IQGAP1 antagonism in epidermal-derived neoplasias as a guide to development of future tumor-selective therapeutics, and B) establish the scope of IQGAP1 necessity in a spectrum of human neoplasias to identify tumor types most likely to be susceptible to inhibition of IQGAP1-mediated processes.