Defining the role and therapeutic implications of altered Notch signaling in oral cancer.

定义 Notch 信号改变在口腔癌中的作用和治疗意义。

• 批准号: 9328488
• 负责人: Kayla M Harmeyer
• 金额: $ 6.06万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9328488
• 关键词: Address; CD44 gene; Cell Maintenance; Cell physiology; Cells; Cessation of life; Conflict (Psychology); Data; Development; Diagnosis; Disease; Dominant-Negative Mutation; Drug Targeting; Drug resistance; Epigenetic Process; Feedback; Foundations; Genes; Goals; KDM5B gene; Ligands; Link; Maintenance; Malignant Epithelial Cell; Mediating; Mentorship; Modeling; Monitor; Mutation; Oncogenic; Oral; Pathway interactions; Patients; Phenotype; Plasticizers; Population; Prevalence; RNA; Reactive Oxygen Species; Regulation; Repression; Resistance; Role; Signal Transduction; Stem cells; Testing; Therapeutic; Treatment Efficacy; Tumor Suppressor Proteins; United States; Up-Regulation; Xenograft procedure; aldehyde dehydrogenase 1; base; cancer stem cell; cancer type; carcinogenesis; career development; chromatin immunoprecipitation; collaborative approach; cytotoxic; design; gamma secretase; gene repression; global health; histone demethylase; improved; in vivo; inducible gene expression; inhibitor/antagonist; innovation; loss of function mutation; malignant mouth neoplasm; mouth squamous cell carcinoma; mutant; neoplastic cell; notch protein; novel therapeutic intervention; predictive modeling; promoter; self-renewal; stem; stem-like cell; tumor; tumor heterogeneity; tumor initiation; tumor progression

PROJECT SUMMARY Oral squamous cell carcinomas (OSCCs) have been proposed to exploit aspects of normal stem cell self- renewal and differentiation to drive cancer progression. Accordingly, activation of the Notch developmental pathway in OSCC has been implicated in cancer stem cell (CSC) function and drug resistance, suggesting that targeted inhibition of the pathway may be an effective therapeutic approach. However, the prevalence of Notch loss-of-function mutations in OSCC tumors also suggests that in certain contexts the Notch pathway may function as a tumor suppressor. The contexts in which Notch activation functions to promote or repress tumor progression are unknown and may dictate how Notch inhibitors can be used in the treatment of OSCC. We have identified two distinct but related OSCC populations with differential Notch pathway activation that may begin to address the distinct functions of the Notch pathway in relation to intra-tumor heterogeneity. Similar to other cancer types, we have isolated and characterized a subset of OSCC cells that reside in a quiescent, “G0- like” state. These G0-like cells have low levels of total RNA and reactive oxygen species (ROS), are drug resistant, and activate the Notch pathway. Though G0-like cells lack upregulation of conventional CSC markers, including CD44 and ALDH1, they are able to transition to a slow-cycling CSC population identified by high expression of the histone demethylase JARID1B. Thus, Notch activation in G0-like cells may potentiate oral CSC function by promoting this transition to a JARID1Bhigh CSC state. As G0-like cells transition to the JARID1Bhigh state Notch pathway activation is reduced, suggesting that Notch pathway repression is required for JARID1Bhigh cells to exert stem cell-like function. Our preliminary data indicate that JARID1B functions to repress Notch signaling by regulating the expression of the Notch ligand JAG1. Therefore, our overall hypothesis is that Notch signals initiate entry of G0-like cells to a JARID1Bhigh state, where JARID1B- mediated suppression of the pathway is required for stem cell-like function. To test this hypothesis, we will first determine the functional role of Notch pathway activation in oral CSC maintenance (Aim 1). Here we will determine the effect of Notch activation or repression on the size and stem-like function of the G0-like population and characterize the requirement for Notch signaling in the G0-like to JARID1Bhigh transition. Additional mechanistic studies will be performed to elucidate the JARID1B-dependent regulation of Notch signaling and to determine the pathway’s role in the stem-cell like function of the JARID1Bhigh population (Aim 2). Taken together, these studies will define context-specific function for Notch signaling that will lead to much needed new therapeutic strategies to achieve lasting OSCC control. A carefully designed career-development and mentorship plan will facilitate the execution of the proposed studies.

项目总结 口腔鳞状细胞癌(OSCCs)已被提出利用正常干细胞自身的某些方面。 更新和分化以推动癌症的进展。因此，Notch发育的激活 口腔鳞癌中的通路与肿瘤干细胞(CSC)的功能和耐药性有关，提示 靶向抑制该通路可能是一种有效的治疗方法。然而，Notch的流行 口腔鳞癌肿瘤中的功能丧失突变也表明，在某些情况下，Notch通路可能 发挥肿瘤抑制因子的作用。Notch激活促进或抑制肿瘤的背景 进展尚不清楚，可能决定了Notch抑制剂如何用于口腔鳞癌的治疗。我们 已经确定了两个不同但相关的口腔鳞状细胞癌群体，它们具有不同的Notch途径激活，可能 开始讨论Notch通路与肿瘤内异质性相关的不同功能。类似于 对于其他类型的癌症，我们分离并鉴定了一组口腔鳞状细胞癌细胞，它们位于静止的G0- 就像“国家。这些G0样细胞具有低水平的总RNA和活性氧物种(ROS)，是药物 抵抗，并激活Notch途径。尽管类G0细胞缺乏常规CSC的上调作用 包括CD44和ALDH1在内的标记，它们能够过渡到由 组蛋白去甲基酶JARID1B的高表达。因此，类G0细胞中的Notch激活可能会增强 口服CSC通过促进这种向JARID1BHIGH CSC状态的转变而发挥作用。当类G0细胞过渡到 JARID1B高态Notch通路激活减少，提示需要抑制Notch通路 JARID1BHigh细胞发挥干细胞样功能。我们的初步数据表明，JARID1B具有 通过调节Notch配体JAG1的表达抑制Notch信号转导。因此，我们的整体 假设Notch信号启动类G0细胞进入JARID1B高状态，其中JARID1B- 干细胞样功能需要介导性抑制该途径。为了检验这一假设，我们 将首先确定Notch通路激活在口腔CSC维持中的功能作用(目标1)。在这里我们 将确定Notch的激活或抑制对G0样蛋白的大小和干样功能的影响 填充并描述类G0到JARID1B高转换中对Notch信令的要求。 将进行其他机制研究，以阐明JARID1B对Notch的依赖调节 并确定该通路在JARID1B高种群(AIM)的干细胞样功能中的作用 2)。综上所述，这些研究将定义Notch信令的上下文特定功能，这将导致 需要新的治疗策略来实现口腔鳞癌的持久控制。精心设计的职业发展 和导师计划将促进拟议研究的执行。