Contribution of G0-like Cells to Maintenance of the Oral Cancer Stem Cell Pool

G0 样细胞对维持口腔癌干细胞库的贡献

• 批准号: 8867033
• 负责人: Nicole D. Facompre
• 金额: $ 3.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867033
• 关键词: Accounting; Affect; Automobile Driving; Biological Assay; Cell Line; Cell physiology; Cells; Cessation of life; Dependence; Development; Differentiation Antigens; Drug Targeting; Drug resistance; Exhibits; Foundations; Frequencies; Goals; Growth; Human; Hyperactive behavior; In Vitro; Individual; KDM5B gene; Maintenance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Modeling; Molecular; Pathway interactions; Patients; Phenotype; Population; Property; Public Health; Recurrence; Relative (related person); Reporter; Resistance; Role; Signal Pathway; Signal Transduction; Stem cells; Supporting Cell; Survivors; System; Testing; Therapeutic; Tumorigenicity; Variant; Work; Xenograft procedure; base; cancer stem cell; cell type; disability; histone demethylase; in vivo; inhibitor/antagonist; innovation; insight; malignant mouth neoplasm; molecular marker; mouth squamous cell carcinoma; neoplastic cell; novel; public health relevance; self-renewal; small hairpin RNA; small molecule; stem cell differentiation; stem cell population; trait; tumor; tumor growth

DESCRIPTION (provided by applicant): Oral squamous cell carcinomas (OSCCs) are proposed to contain a subset of tumor cells whose stem cell-like molecular and functional properties are required to sustain tumor growth. In a hierarchical model, these cancer stem cells (CSCs) are the only cells with unlimited self-renewal capacity and thus may be targeted in isolation to achieve tumor control. However, there is increasing evidence that some non-CSCs have the phenotypic plasticity to return to the CSC pool and thus retain therapeutic relevance. Accurately defining non-CSCs that can support an oral CSC pool together with mechanisms that drive these cells toward a CSC state would establish novel paradigm for OSCC treatment. Our preliminary work has isolated OSCC cells residing in a "G0- like" cell state previously found to have high growth potential, innate drug resistance, and low levels of Akt. Despite lacking molecular markers of CSCs, these cells displayed high tumorigenicity in vivo. Our working hypothesis is that the functional properties of G0-like cells reflect their ability to transition t a CSC state. We have also identified a putative CSC population in OSCCs, based on high expression JARID1B, a histone demethylase known to maintain other malignant and normal stem cell phenotypes. JARID1Bhigh cells exhibit both functional and molecular stem cell traits and are further distinguished from the G0-like subset by hyper- activation of the PI3K-Akt signaling pathway. To explain these findings, our overall hypothesis is that reactivation of the PI3K-Akt pathway in G0-like cells supports their return to the CSC pool by driving their transition to a JARID1Bhigh state. To test this hypothesis, we will first test the roles of the JARID1Bhigh and G0- like subsets in OSCC growth using conventional CSC molecular and functional criteria (aim 1). We will specifically test whether JARID1Bhigh cells have independent CSC functions, while tumor formation by G0-like cells may depend upon the JARID1Bhigh fraction. Additional studies will elucidate how PI3K-Akt signals regulate transitions among CSCs, G0-like cells, and the broader non-CSC pool (aim 2). Here we will test whether modulation of the PI3K-Akt pathway affects the sizes of the G0-like and JARID1Bhigh pools and/or the ability of non-CSCs to transition toward a JARID1Bhigh CSC state. Together these studies would provide valuable insight into the hierarchical organization and plasticity of non-CSC and CSC subsets within OSCCs.

描述（由申请人提供）：口腔鳞状细胞癌（OSCC）被认为含有一个肿瘤细胞亚群，其干细胞样分子和功能特性是维持肿瘤生长所必需的。 在分层模型中，这些癌症干细胞（CSC）是唯一具有无限自我更新能力的细胞，因此可以单独靶向以实现肿瘤控制。 然而，越来越多的证据表明，一些非CSC具有表型可塑性，可以返回CSC库，从而保持治疗相关性。 准确定义可以支持口腔CSC池的非CSC以及驱动这些细胞朝向CSC状态的机制将建立OSCC治疗的新范例。我们的初步工作已经分离出了居住在“G 0样”细胞状态的OSCC细胞，这些细胞先前被发现具有高生长潜力、先天耐药性和低水平的Akt。 尽管缺乏CSC的分子标记，这些细胞在体内显示出高致瘤性。我们的工作假设是，G 0样细胞的功能特性反映了它们向CSC状态转变的能力。 我们还确定了一个假定的CSC人口OSCC的基础上，高表达JARID 1B，组蛋白脱甲基酶已知维持其他恶性和正常的干细胞表型。JARID 1Bhigh细胞表现出功能性和分子干细胞特性，并且通过PI 3 K-Akt信号传导途径的超活化进一步与G 0样亚群区分开。为了解释这些发现，我们的总体假设是，G 0样细胞中PI 3 K-Akt通路的重新激活通过驱动它们的转换支持它们返回CSC池。 到JARID 1B高状态。 为了验证这一假设，我们将首先使用传统的CSC分子和功能标准测试JARID 1Bhigh和G 0样亚群在OSCC生长中的作用（目的1）。我们将专门测试JARID 1Bhigh细胞是否具有独立的CSC功能，而G 0样细胞的肿瘤形成可能取决于JARID 1Bhigh组分。其他研究将阐明PI 3 K-Akt信号如何调节CSC、G 0样细胞和更广泛的非CSC池之间的转换（目的2）。 在这里，我们将测试PI 3 K-Akt通路的调节是否影响G 0样和JARID 1Bhigh池的大小和/或非CSC向JARID 1Bhigh CSC状态转变的能力。 总之，这些研究将提供有价值的洞察OSCC内的非CSC和CSC子集的层次组织和可塑性。