Activin A signaling regulates head and neck squamous cell carcinoma invasion and metastasis

激活素A信号调节头颈鳞状细胞癌的侵袭和转移

基本信息

批准号：
9117122
负责人：
Holli Loomans-Kropp
金额：
$ 2.9万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9117122
关键词：
Activin Receptor Age Alcohol consumption Apoptosis Binding Biological Assay Cancer cell line Cell Cycle Arrest Cells Cessation of life Characteristics Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Complex Data Detection Development Diagnosis Diagnostic Disease Down-Regulation Elements Embryonic Development Endoderm Epidemiology Epithelial Cells Esophageal Squamous Cell Esophageal Squamous Cell Carcinoma Excision Fibroblasts Gender Gene Expression Genetic Transcription Goals Growth Growth and Development function Head and Neck Squamous Cell Carcinoma Human Human papilloma virus infection INHBA gene Immunofluorescence Immunologic Immunohistochemistry In Vitro Incidence Individual Injection of therapeutic agent Invaded Knowledge Laboratories Ligands Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediating Mesoderm Mission Modeling Molecular Monitor Mus Nature Neoplasm Metastasis Normal tissue morphology Nude Mice Output Pathway interactions Patients Pattern Phenotype Process Prognostic Marker Proteins Public Health Radiation therapy Recombinants Recurrence Research Resistance Risk Factors Sampling Severities Signal Pathway Signal Transduction Smad Proteins Smad protein Staging Survival Rate Tail Techniques Therapeutic Tissues Tobacco use Transforming Growth Factor beta Tumor Angiogenesis Tumor Cell Invasion Type I Activin Receptors United States United States National Institutes of Health Up-Regulation Veins Western Blotting activin A angiogenesis arm cancer cell cancer diagnosis cell motility cell stroma cigarette smoking colon cancer patients diagnostic biomarker high risk human disease in vivo male malignant breast neoplasm migration mouse model mouth squamous cell carcinoma neoplastic cell outcome forecast overexpression pancreatic cancer cells prognostic significance protein expression public health relevance receptor research study response stem cell fate treatment effect tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Though this group of cancers is not among the most prevalent in the United States, the incidence rate of HNSCC has steadily increased over the last decade while the 5-year survival rate has remained static. Though there is a general understanding of the risk factors for HNSCC initiation, such as cigarette smoking and alcohol consumption, there is little knowledge regarding the mechanisms of HNSCC progression, particularly modes of invasion and metastasis. Loss of response to Activin A (Act A) signaling, an arm of the TGFβ superfamily, has been recently implicated in cancer progression and metastasis. Characteristic Act A signaling has been found to promote apoptosis and growth arrest, as well as potently inhibit angiogenesis. However, Act A expression is commonly upregulated in tumors, compared to normal tissue. This clinical evidence suggests that the cancer cells may acquire resistance to Act A signaling, such as through alterations of proteins involved in the signaling cascade, therefore rendering the cells insensitive to the growth inhibitory effects of Act A. Loss of tumor cell response to Act A signaling may be a result of a downregulation of one or multiple components of the Act A signaling cascade. Evidence from breast and colorectal cancer patient samples have demonstrated a decrease in expression of activin receptor type I, with a concurrent increase in Act A secretion, occurring in a stage- and grade-dependent manner. Additionally, pancreatic cancer cell lines with loss of activin receptor type IB (ALK4) are unresponsive to Act A stimulation, while cells that have intact signaling undergo growth arrest. Preliminary data from our laboratory has demonstrated that dysplastic esophageal squamous cells with intact Act A signaling show less migration, invasion, and proliferation when co-cultured with fibroblasts that stably overexpress Act A, compared to control. However, when esophageal squamous cell carcinoma (ESCC) cells with unaltered Act A signaling are co-cultured long-term with fibroblasts that stably overexpress Act A, the carcinoma cells downregulate ALK4 in response to continious Act A stimulation. As models of ESCC and HNSCC are physiologically similar, we have extrapolated the results we attained regarding the action of Act A in ESCC to HNSCC. Therefore, we hypothesize that loss of cellular responsiveness to Act A through alteration of constituents of the Act A signaling cascade, such as through the downregulation of ALK4, in HNSCC renders the cells insensitive to the growth inhibitory effects of Act A, promoting an invasive cancer phenotype. We will first determine the functional consequences of loss of cellular responsiveness to Act A signaling on HNSCC cell migration and invasion in vitro, using CRISPR-mediated deletion of ALK4 to specifically target Act A signaling. As the tumor microenvironment is critical for cancer progression, we will investigate how disruption of Act A signaling in vivo impacts cancer cell invasion and metastasis. Upon completion of these experiments, we will have determined the nature of Act A signaling in HNSCC and its contribution to cancer progression. Ultimately, these results will aid on the discovery of better diagnostic and prognostic biomarkers for HNSCC.

描述（由申请人提供）：头颈鳞状细胞癌 (HNSCC) 是全球第六大常见癌症，尽管这类癌症在美国并不是最常见的癌症之一，但 HNSCC 的发病率近年来一直在稳步上升。尽管人们对 HNSCC 发生的危险因素（例如吸烟和饮酒）有普遍了解，但 5 年生存率却保持不变，但对 HNSCC 进展的机制，特别是发病模式知之甚少。最近发现，激活素 A (Act A) 信号传导（TGFβ 超家族的一个分支）的反应丧失与癌症进展和转移有关，可促进细胞凋亡和生长停滞。然而，与正常组织相比，Act A 表达通常在肿瘤中上调，该临床证据表明癌细胞可能获得对 Act A 信号传导的抵抗，例如通过改变参与信号传导的蛋白质。级联反应，因此使细胞对 Act A 的生长抑制作用不敏感。肿瘤细胞对 Act A 信号传导反应的丧失可能是 Act A 信号传导级联的一个或多个成分下调的结果。来自乳腺癌和结直肠癌的证据。患者样本已证明 I 型激活素受体表达减少，同时 Act A 分泌增加，并且以阶段和级别依赖性方式发生。另外，IB 型激活素受体缺失的胰腺癌细胞系。 (ALK4) 对 Act A 刺激无反应，而具有完整信号传导的细胞则生长停滞，我们实验室的初步数据表明，具有完整 Act A 信号传导的发育不良食管鳞状细胞在与 Act A 信号共培养时表现出较少的迁移、侵袭和增殖。与对照相比，成纤维细胞稳定过度表达 Act A 然而，当共培养 Act A 信号未改变的食管鳞状细胞癌 (ESCC) 细胞时。长期稳定过表达 Act A 的成纤维细胞，癌细胞会响应连续的 Act A 刺激而下调 ALK4，由于 ESCC 和 HNSCC 模型在生理上相似，因此我们将我们获得的有关 Act A 在 ESCC 中的作用的结果推断为：因此，我们通过改变 Act A 信号级联的组成部分（例如通过下调 ALK4）来追踪细胞对 Act A 反应性的丧失。 HNSCC 使细胞对 Act A 的生长抑制作用不敏感，从而促进侵袭性癌症表型。我们将首先使用 CRISPR 介导的缺失来确定细胞对 Act A 信号传导丧失反应性对 HNSCC 细胞迁移和侵袭的功能影响。由于肿瘤微环境对于癌症进展至关重要，因此我们将研究体内 Act A 信号传导的破坏如何影响癌细胞的侵袭和转移。完成这些实验后，我们将确定其性质。 A 幕最终，这些结果将有助于发现更好的 HNSCC 诊断和预后生物标志物。