Elucidating IL-6/STAT3-mediated Phenotypic Changes in Head and Neck Cancer Stem Cells

阐明头颈癌干细胞中 IL-6/STAT3 介导的表型变化

• 批准号: 10458568
• 负责人: Alexandra Eileen Herzog
• 金额: $ 5.26万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458568
• 关键词: Antibodies; Body mass index; CD44 gene; CRISPR/Cas technology; Cell Fraction; Cell Line; Cell division; Cell physiology; Cells; Characteristics; Cisplatin; Colony-Forming Units Assay; Data; Development; Developmental Therapeutics Program; Endothelial Cells; Exhibits; FDA approved; Frequencies; Genetic; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; IL-6 inhibitor; In Vitro; Interleukin-6; Laboratories; Maintenance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Neoplasm Metastasis; Parents; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Platinum; Population; Process; Property; Proteins; Quality of life; RNA; Recurrence; Regulation; Reporter; Residual Tumors; Residual state; Resistance; Rheumatoid Arthritis; STAT3 gene; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Therapeutic Studies; Time; Work; aldehyde dehydrogenases; base; cancer cell; cancer heterogeneity; cancer stem cell; cell motility; chemotherapeutic agent; chemotherapy; head and neck cancer patient; improved; in vitro Assay; in vivo; insight; mouse model; neoplastic cell; novel; offspring; patient derived xenograft model; prevent; self-renewal; stem; stem cell function; stem cell niche; stem cell population; stem cell proliferation; stem cell self renewal; stemness; therapy resistant; tocilizumab; tumor; tumor growth; tumor initiation; tumorigenic

ABSTRACT Head and neck squamous cell carcinoma (HNSCC) is a frequent and deadly malignancy. Despite significant advances in the understanding of the pathobiology of HNSCC, the substantial patient morbidity associated with treatment and the high frequency of tumor recurrence/metastasis result in an unacceptably low patient survival and poor quality of life. The cancer stem cell (CSC) hypothesis attempts to explain the observed heterogeneity of cancer cells within a tumor, with many malignant features of a cancer cell deriving from a shift towards stem- like features. CSCs function as drivers of tumor initiation, therapeutic evasion, and recurrence in HNSCC. Platinum-based agents such as Cisplatin have been shown to enhance the CSC fraction and self-renewal, as determined by Bmi-1 expression. Head and neck CSCs rely on cellular crosstalk within the perivascular niche, particularly on endothelial cell-secreted IL-6. Our preliminary data showed that IL-6/STAT3 inhibition prevents Cisplatin-induced CSC self-renewal. But the mechanism through which inhibition of IL-6 signaling asserts this function and its implications on therapeutic resistance and tumor recurrence remain unclear. The long-term objective of this project is to study molecular mechanisms underlying the acquisition and maintenance of the stem-like cancer cell phenotype. The overall hypothesis of this work is that therapeutic blockade of the IL- 6/STAT3 pathway suppresses the Bmi-1-mediated CSC self-renewal and inhibits HNSCC recurrence. To test this hypothesis, we propose the following specific aims: 1) to elucidate mechanisms underlying IL-6/STAT3- mediated phenotypic changes in the cancer cell population, 2) to describe the real-time effect of IL-6/STAT3 inhibition and Cisplatin therapy on CSC proliferation patterns, and 3) to determine the effect of inhibiting CSC self-renewal on resistance to conventional Cisplatin therapy and recurrence in HNSCC. To accomplish these aims, both genetic and pharmacologic approaches will be used in CSC assays in vitro and in vivo to test the hypothesis that the CSC phenotype is regulated by Bmi-1 via IL-6/STAT3 signaling. We will investigate the real- time phenotypic changes within the CSC population using a CRISPR/Cas9 reporter system to test the hypothesis that IL-6/STAT3 inhibition promotes asymmetric cell division of CSC by decreasing their self-renewal. Cisplatin- resistant cell lines and patient-derived xenograft mouse models will be used to test the hypothesis that inhibiting IL-6/STAT3 signaling will overcome evasive resistance to Cisplatin and prevent tumor recurrence. Elucidating crucial mechanisms that define the fate of head and neck cancer stem cells will inform mechanism-based therapies that have the potential to enhance the survival and quality of life of patients with head and neck cancer.

抽象的 头部和颈部鳞状细胞癌（HNSCC）是一种频繁而致命的恶性肿瘤。尽管很重要 对HNSCC病理生物学的理解的进步，与HNSCC的病理生物学有关 治疗和肿瘤复发/转移的高频导致患者的生存率低下 和生活质量差。癌症干细胞（CSC）假设试图解释观察到的异质性 肿瘤内的癌细胞的许多恶性特征，癌细胞的许多恶性特征是从向茎转移的 喜欢功能。 CSC在HNSCC中充当肿瘤起始，治疗逃避和复发的驱动因素。 铂类药物（例如顺铂）已被证明可以增强CSC的分数和自我更新，如 由BMI-1表达确定。头部和颈CSC依赖于血管周期内的细胞串扰， 特别是在内皮细胞分泌的IL-6上。我们的初步数据表明，IL-6/STAT3抑制可防止 顺铂诱导的CSC自我更新。但是抑制IL-6信号传导的机制断言了这一点 功能及其对治疗性抗性和肿瘤复发的影响尚不清楚。长期 该项目的目的是研究获得和维护的基础的分子机制 茎状癌细胞表型。这项工作的总体假设是对IL-的治疗阻滞 6/STAT3途径抑制BMI-1介导的CSC自我更新并抑制HNSCC复发。到 检验该假设，我们提出以下具体目的：1）阐明IL-6/STAT3-的机制 癌细胞种群中介导的表型变化，2）描述IL-6/STAT3的实时效应 抑制和顺铂治疗CSC增殖模式，3）确定抑制CSC的影响 HNSCC中对常规顺铂治疗和复发的抗性自我更新。完成这些 目的，遗传和药理方法将在体外和体内用于CSC分析中，以测试 假设CSC表型受BMI-1通过IL-6/STAT3信号传导调节。我们将调查现实 - 使用CRISPR/CAS9记者系统在CSC种群中的时间表型变化来检验假设 IL-6/STAT3抑制通过减少自我更新来促进CSC的不对称细胞分裂。顺铂 耐药细胞系和患者衍生的异种移植小鼠模型将用于测试抑制的假设 IL-6/STAT3信号传导将克服对顺铂的反射抗性并防止肿瘤复发。阐明 定义头颈癌干细胞命运的关键机制将为基于机制的命运提供信息 具有增强头颈癌患者生存率和生活质量的疗法。