Role of TGFbeta signaling in HNSCC progression

描述（由申请人提供）：长期目标是确定可用于HNSCC预后和治疗的分子靶点。头颈部鳞状细胞癌（HNSCC）是西方国家第六大常见癌症类型。HNSCC的主要病因是环境致癌物，如烟草和酒精，它们会导致头颈部组织的遗传改变和慢性炎症。在本应用中，我们将使用可诱导的H&N特异性基因靶向系统，将TGF¿信号通路中常见的几种基因改变引入小鼠H&N组织，并评估这些改变促进HNSCC发展的机制。目的1将研究Smad4缺失介导的HNSCC发展的分子机制。我们将评估是否有任何Fanc/Brca成员是Smad4的直接转录靶点，以及Smad4-/- HNSCCs中的VEGF过表达是否是Smad3激活的结果，并有助于Smad4缺失介导的HNSCC癌变。将进行全基因组分析，以确定Smad4缺失引起的其他改变，这有助于对H&N上皮和间质的致癌作用。目的2将评估Smad2缺失在HNSCC促进中的作用。我们将确定Smad2缺失是否会在Kras突变的情况下促进HNSCC的形成和进展。我们将分析在Smad2-/-组织中发现的HGF信号增加是否有助于Smad2缺失相关的致癌作用，并研究Smad2-/-细胞中HGF上调的机制。还将进行全基因组筛选，以确定H&N组织中Smad2丢失引起的分子改变。目的3将评估间质TGF - RII缺失在HNSCC发展中的作用。我们将在口腔成纤维细胞中诱导TGF¿RII缺失，以确定在化学致癌物质诱导的H-ras突变或H&N上皮中TGF¿RII缺失的情况下，这是否会诱导或促进HNSCC的形成。分析口腔成纤维细胞TGF¿RII缺失引起的病理和分子改变。这些研究不仅将提高我们对HNSCC生物学的理解，而且将直接测试具有特定TGF¿信号缺陷的HSNCC的治疗方法。

DESCRIPTION (provided by applicant): The long term goal is to identify molecular targets that can be used for prognosis and therapy of HNSCC. Head & neck squamous cell carcinomas (HNSCC) represent the 6th most common cancer type in western countries. The major HNSCC etiological factors are environmental carcinogens, e.g., tobacco and alcohol, which cause genetic alterations and chronic inflammation in head & neck (H&N) tissues. In this application, we will use an inducible H&N-specific gene targeting system to introduce several genetic alterations in the TGF¿ signaling pathway, which are common in human HNSCC, into mouse H&N tissues, and assess the mechanisms by which these alterations promote HNSCC development. Aim 1 will examine molecular mechanisms of Smad4 loss-mediated HNSCC development. We will assess if any Fanc/Brca members are direct Smad4 transcriptional targets, and if VEGF overexpression in Smad4-/- HNSCCs is the result of Smad3 activation and contributes to Smad4 loss-mediated HNSCC carcinogenesis. Genome-wide analyses will be performed to identify additional alterations caused by Smad4 loss, which contribute to oncogenic effects on H&N epithelia and stroma. Aim 2 will assess the role of Smad2 loss in HNSCC promotion. We will determine if Smad2 loss promotes HNSCC formation and progression in the presence of a Kras mutation. We will analyze if increased HGF signaling found in Smad2-/- tissues contributes to Smad2 loss-associated oncogenic effects and study the mechanisms of HGF upregulation in Smad2-/- cells. Genome-wide screens will also be performed to identify molecular alterations caused by Smad2 loss in H&N tissues. Aim 3 will assess the role of stromal TGF¿RII loss in HNSCC development. We will induce TGF¿RII deletion in oral fibroblasts to ascertain if this will induce or promote HNSCC formation in the presence of either a chemical carcinogen-induced H-ras mutation or TGF¿RII deletion in H&N epithelia. Pathological and molecular alterations caused by oral fibroblast TGF¿RII deletion will be analyzed. These studies will not only improve our understanding of HNSCC biology, but will also directly test therapeutic approaches in HSNCC with specific TGF¿ signaling defects. PUBLIC HEALTH RELEVANCE: The application will use state-of-the-art experimental models and approaches to identify molecular mechanisms that cause head & neck cancer formation and progression. The proposed studies will lead to the identification of biomarkers that can be used to improve cancer prognosis and therapy.