MAPK pathway modulation in thyroid tumorigenesis

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。

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.