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

• 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
• 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

 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（由适用提供）：头部和颈部鳞状细胞癌（HNSCC）是全球第六个最常见的癌症。尽管这组癌症不是美国最普遍的癌症，但HNSCC的事件率在过去十年中悄悄提高，而5年的生存率仍然是静态的。尽管人们对HNSCC倡议的风险因素（例如吸烟和饮酒）有一般的了解，但关于HNSCC进展的机制，尤其是入侵和转移模式的知识很少。最近与癌症的进展和转移有关，对激活素A（ACT A）信号传导的反应丧失。特征ACT A信号传导已被发现促进凋亡和生长停滞，并可能抑制血管生成。但是，与正常组织相比，ACT A表达通常在肿瘤中更新。该临床证据表明，癌细胞可能会获得对信号传导的抵抗力，例如通过改变信号传导级联反应的蛋白质的改变，因此使细胞对ACT A的生长抑制作用不敏感。ACTA的生长抑制作用A的损失可能是ACT A ACT A信号的丧失可能是对ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT ACT cascade的结果。乳腺癌和结直肠癌患者样本的证据表明，激活素受体I型的表达降低，并以阶段依赖性的方式同时增加了ACT A分泌的同时增加。此外，胰岛受体IB型（ALK4）损失的胰腺癌细胞系无反应，而具有完整信号传导的细胞会经历生长停滞。我们实验室的初步数据表明，与对照组相比，与成纤维细胞共同培养的成纤维细胞与对照组合相比，具有稳定过表达ACTA的成纤维细胞时，具有完整动作的食管食管鳞状细胞显示出较少的迁移，侵袭和增殖。然而，当具有未改变的作用A信号传导的食管鳞状细胞癌（ESCC）细胞与稳定过表达A作用A的成纤维细胞共培养A信号传导时，癌细胞癌细胞响应连续ACT A刺激而下调ALK4。由于ESCC和HNSCC的模型在生理上是相似的，因此我们推断了有关ACC在ESCC中对HNSCC的作用的结果。因此，我们假设通过改变ACT A信号级联的一致性（例如通过ALK4的下调）在HNSCC中，对ACT A的作用A的丧失使细胞对ACT A的生长抑制作用不敏感，从而促进了侵袭性癌症表型。我们将首先使用CRISPR介导的ALK4的缺失来专门针对ACT A信号传导，从而确定细胞反应能力丧失对HNSCC细胞迁移和体外侵袭的作用A信号的功能后果。由于肿瘤微环境对于癌症的进展至关重要，我们将研究ACT A ACT在体内的破坏如何影响癌细胞侵袭和转移。这些实验完成后，我们将确定HNSCC中ACT A信号的性质及其对癌症进展的贡献。最终，这些结果将有助于发现HNSCC更好的诊断和预后生物标志物。