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: 10677881
• 负责人: Alexandra Eileen Herzog
• 金额: $ 5.15万
• 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/10677881
• 关键词: Antibodies; Blood Vessels; CD44 gene; CRISPR/Cas technology; Cell Fraction; Cell Line; Cell division; Cell physiology; Cell secretion; 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 Neoplasms; Mediating; Mediator; Modeling; Molecular; Morbidity - disease rate; Neoplasm Metastasis; Parents; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Platinum; Population; Process; Property; Proteins; Quality of life; RNA; Recurrence; Recurrent tumor; Regulation; Reporter; Residual Neoplasm; Residual state; Resistance; Rheumatoid Arthritis; STAT3 gene; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Therapeutic Studies; Time; Work; aldehyde dehydrogenases; cancer cell; cancer heterogeneity; cancer stem cell; carcinogenesis; 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; pharmacologic; 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 头颈鳞状细胞癌（HNSCC）是一种常见且致命的恶性肿瘤。尽管显着 对 HNSCC 病理学理解的进展，与 HNSCC 相关的大量患者发病率 治疗和肿瘤复发/转移的高频率导致患者生存率低得令人无法接受 和生活质量差。癌症干细胞（CSC）假说试图解释观察到的异质性 肿瘤内癌细胞的许多恶性特征源于干细胞的转变 喜欢特征。 CSC 是 HNSCC 肿瘤发生、治疗逃避和复发的驱动因素。 铂基药物（例如顺铂）已被证明可以增强 CSC 分数和自我更新，因为 由 Bmi-1 表达确定。头颈 CSC 依赖于血管周围微环境内的细胞串扰， 特别是内皮细胞分泌的 IL-6。我们的初步数据表明，IL-6/STAT3 抑制可预防 顺铂诱导 CSC 自我更新。但抑制 IL-6 信号传导的机制证实了这一点 其功能及其对治疗耐药和肿瘤复发的影响仍不清楚。长期来看 该项目的目标是研究获得和维持的分子机制 干细胞样癌细胞表型。这项工作的总体假设是，治疗性阻断 IL- 6/STAT3 通路抑制 Bmi-1 介导的 CSC 自我更新并抑制 HNSCC 复发。到 为了检验这一假设，我们提出以下具体目标：1）阐明IL-6/STAT3-的潜在机制 介导的癌细胞群表型变化，2) 描述 IL-6/STAT3 的实时效果 抑制和顺铂治疗对CSC增殖模式的影响，以及3)确定抑制CSC的效果 自我更新对传统顺铂治疗的耐药性和 HNSCC 的复发。为了完成这些 的目标，遗传和药理学方法将用于 CSC 体外和体内测定，以测试 假设 CSC 表型由 Bmi-1 通过 IL-6/STAT3 信号传导调节。我们将调查真实情况—— 使用 CRISPR/Cas9 报告系统检测 CSC 群体内表型变化的时间来检验假设 IL-6/STAT3 抑制通过减少 CSC 的自我更新来促进 CSC 的不对称细胞分裂。顺铂- 耐药细胞系和患者来源的异种移植小鼠模型将用于检验抑制 IL-6/STAT3 信号传导将克服对顺铂的逃避耐药性并防止肿瘤复发。阐明 定义头颈癌干细胞命运的关键机制将为基于机制的研究提供信息 有潜力提高头颈癌患者的生存率和生活质量的疗法。