权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MAPK pathway modulation in thyroid tumorigenesis

MAPK 通路调节甲状腺肿瘤发生

基本信息

批准号：
10524084
负责人：
Aime T Franco
金额：
$ 7.03万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524084
关键词：
Affect Benign Biological Models Cells Clinical Collagen Coupled Data Development Disease Disease Progression Distant Endocrine Endothelial Cells Epithelial Event Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Follicular thyroid carcinoma Genetic Human Immune In Vitro Incidence Lead MAP Kinase Gene MAPK Signaling Pathway Pathway Malignant Neoplasms Malignant neoplasm of thyroid Modeling Modification Molecular Mutation Neoplasm Metastasis Non-Malignant Oncogene Activation Oncogenic Outcome Papillary thyroid carcinoma Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Phenotype Prevention Prevention strategy Primary Neoplasm Proteins RAS genes Research Proposals Role Sampling Signal Pathway Signal Transduction Site Solid Solid Neoplasm Stromal Cells Stromal Change Stromal Neoplasm Therapeutic Thyroid Diseases Thyroid Gland Tissues Tumor Cell Line Tumor Subtype adenoma anaplastic thyroid cancer biomarker identification cancer diagnosis clinical practice crosslink extracellular human disease in vitro Model in vivo migration mouse model neoplastic cell new therapeutic target novel novel therapeutics predictive marker recruit response thyroid neoplasm tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Thyroid cancer is the most common endocrine malignancy and incidences are rising. Thyroid cancers of follicular cell origin stand out among solid tumors because many of the tumor-initiating genetic events are known. Activating mutations of effectors of the MAPK signaling pathway are associated with both follicular and papillary thyroid cancer, and occur throughout the spectrum of thyroid diseases from benign adenomas through therapeutically refractive poorly-differentiated disease. Despite sharing activation of the MAPK pathway, activation via different effectors in the pathway results in distinct and unique pathological outcomes, including metastasis to distinct distant sites. We do not understand how activation of a single pathway via different mutations within the signaling cascade results in different pathological outcomes and recruitment of different tumor microenvironments. This paradigm is seen not only in thyroid cancer, but in other malignancies. We will utilize recently generated mouse models of thyroid cancer to model follicular and papillary thyroid cancers to study how activation of the oncogene Hras versus Braf affects tumor development and can modify the tumor microenvironment. We hypothesize that mode of activation contributes to stromal recruitment and extracellular matrix (ECM) modification, thus contributing to the pathobiology of tumor formation and progression. The data generated in these studies will provide a better understanding of the mechanisms by which different oncogenic events that activate the same pathway predisposes the development distinct pathological outcomes. We hope to use these data to develop novel therapeutic and prevention strategies for thyroid cancer.

项目摘要/摘要甲状腺癌是最常见的内分泌恶性肿瘤，发病率呈上升趋势。甲状腺癌滤泡细胞起源在实体瘤中脱颖而出，因为许多启动肿瘤的遗传事件为人所知。MAPK信号通路效应器的激活突变与卵泡和甲状腺乳头状癌，可见于各种甲状腺疾病，包括良性腺瘤通过治疗屈光不正的低分化疾病。尽管分享了MAPK的激活途径，通过途径中不同效应器的激活导致不同和独特的病理结果，包括转移到不同的远端部位。我们不知道单一途径是如何通过信号级联中不同的突变导致不同的病理结果和招募不同的肿瘤微环境。这一范例不仅见于甲状腺癌，而且见于其他恶性肿瘤。我们将利用最近产生的甲状腺癌小鼠模型来模拟滤泡和甲状腺乳头状癌研究癌基因HRAS与BRAF的激活如何影响肿瘤的发展并能改变肿瘤微环境。我们假设激活模式对间质有贡献募集和细胞外基质(ECM)修饰，从而有助于肿瘤的病理生物学形成和发展。这些研究中产生的数据将有助于更好地了解激活同一条通路的不同致癌事件的机制发展出不同的病理结果。我们希望利用这些数据来开发新的治疗和甲状腺癌的预防策略。