Signaling Modulators in Epidermal Carcinogenesis

表皮癌变中的信号调节剂

• 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
• 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

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激酶信号级联的激活是大多数人类恶性肿瘤的共同核心特征，使该途径成为癌症治疗的潜在高价值靶点。然而，直接靶向该途径的典型元件作为治疗方法由于Ras MAPK信号传导在几乎所有人体组织中普遍活跃并且是组织活力所需的事实而导致的全身毒性而复杂化。然而，完整的MAP激酶信号传导需要MAPK相互作用支架蛋白家族的功能，该蛋白家族调节和协调通路输出。最近的数据表明，这些元素之一，IQGAP 1，它调节Erk MAPK活性，？连环蛋白信号传导、细胞骨架重塑和细胞运动对于正常组织发育和体内平衡是必需的，但对于Ras的致癌作用的表现是必需的。该提案旨在定义医学相关人体组织背景下这种肿瘤特异性要求的机制基础。为了实现这一点，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侵袭性表皮瘤形成的原代表皮角质形成细胞表达肿瘤相关的活性Ras，完整的基底膜，和建筑上忠实的天然基质。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，以及通过基底膜侵入支持基质。工程化组织将掺入具有RNAi介导的内源性IQGAP 1拮抗作用的角质形成细胞，并结合不能结合特异性相互作用蛋白的IQGAP 1突变体的表达。这些努力旨在确定哪些IQGAP 1功能对于支持肿瘤侵袭的进展最为关键。这些功能性人体组织研究对于靶向治疗剂的设计将是重要的，并且被构造成允许鉴定肿瘤组织独特需要的其他下游效应物。其次，我们将采用我们实验室开发的其他新的遗传学定义的人类肿瘤模型，这些模型基于来自12种不同组织类型的原代细胞中不同肿瘤相关致癌驱动突变的表达。这些工程肿瘤将在实验中部署，以确定IQGAP 1支架在一系列人类肿瘤类型中的作用。在拟定的资助期结束时，我们的目标是：A）了解IQGAP 1在表皮源性肿瘤中的拮抗作用机制，作为开发未来肿瘤选择性治疗的指南，以及B）确定IQGAP 1在人类肿瘤谱中的必要性范围，以确定最可能对IQGAP 1介导过程抑制敏感的肿瘤类型。