A quiescent G0-like cell state as a barrier to eradication oral cancer stem cells

静止的 G0 样细胞状态是根除口腔癌干细胞的障碍

• 批准号: 8722223
• 负责人: Devraj Basu
• 金额: $ 24.67万
• 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: 2014-07-07 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722223
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Address; Behavior Therapy; Biological Assay; Biological Models; CD44 gene; Cell Fraction; Cell Line; Cell physiology; Cells; Cessation of life; Clinical; Consensus; Data; Dominant-Negative Mutation; Drug Targeting; Drug resistance; Epigenetic Process; Future; Genetic Transcription; Goals; Growth; Histones; Human; KDM5B gene; Link; Malignant Epithelial Cell; Mediating; Modeling; Molecular Profiling; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Property; Proto-Oncogene Proteins c-akt; Public Health; Relative (related person); Reporter; Resistance; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Stem cells; Supporting Cell; Survivors; System; Testing; Treatment Failure; Validation; Video Microscopy; Work; Xenograft procedure; base; cancer cell; cancer stem cell; cancer therapy; cancer type; cell type; disability; improved; in vivo; inhibitor/antagonist; malignant mouth neoplasm; melanoma; mouth squamous cell carcinoma; neoplastic cell; notch protein; novel; prevent; public health relevance; self-renewal; small hairpin RNA; stem cell differentiation; stem cell population; therapeutic target; trait; translational study; tumor; tumor growth

DESCRIPTION (provided by applicant): Although cancer stem cells (CSCs) present an appealing therapeutic target in oral squamous cells carcinomas (OSCCs), a consensus molecular profile for such oral CSCs has not emerged. CSC eradication is further hampered by growing evidence of phenotypic plasticity in some non-CSCs allowing them to return to the CSC pool. Accurately defining oral CSCs together with mechanisms for restoring them after targeted depletion would establish a novel conceptual framework for effective OSCC therapy. Our preliminary work has isolated a drug-resistant subset of slow-cycling JARID1B-hi cells as a candidate CSC population in OSCC. JARID1B, a histone demethylase whose expression identifies CSCs by functional criteria in other cancer types, shows promise as a generalizable CSC marker based on its ability to mediate entry into a stem cell-like epigenetic state. Hyper-activation of the PI3-kinase (PI3K) pathway in JARID1B-hi cells renders them sensitive to depletion by PI3K-targeted drugs. Our working hypothesis is that a depleted JARID1B-hi CSC pool can be replenished by a population of quiescent "G0-like" cells, which have both high growth potential and drug resistance. While lacking the stem cell markers and PI3K pathway activity seen in JARID1B-hi cells, G0-like cells do show prominent Notch pathway activation, which has been linked to CSC population expansion and increased PI3K/AKT signaling. To explain these findings, our overall hypothesis is that entry of proliferative OSCC cells into a quiescent, G0-like state creates a reservoir to prevent permanent CSC depletion by providing a direct precursor to JARID1B-hi cells. To test this hypothesis, we will first test the roles of JARID1B- hi and G0-like subsets in OSCC growth using conventional CSC criteria (aim 1). We will specifically test whether JARID1B-hi cells have independent CSC functions, while tumor formation by G0-like cells may depend upon the JARID1B-hi fraction. Additional studies will define the precise role of G0-like cells in sustaining the JARID1B-hi population in OSCC (aim 2). Here we test whether Notch-mediated entry of non-CSCs into a quiescent G0-like state forms a direct precursor for JARID1B-hi cells, thus providing a reservoir for CSC repopulation. Validation of these concepts here would establish new model systems to dissect mechanisms underlying the cell state transitions that prevent durable oral CSC depletion during treatment. In doing so, our work will also facilitate translational studies to jointly target two distinct tumor cell phenotypes that cooperatively sustain OSCC growth via the Notch and PI3K pathways.

描述（由申请人提供）：尽管癌症干细胞（CSC）在口腔鳞状细胞癌（OSCC）中呈现出有吸引力的治疗靶点，但尚未出现此类口腔CSC的一致分子谱。越来越多的证据表明，一些非CSC的表型可塑性允许它们返回CSC库，这进一步阻碍了CSC的根除。准确定义口腔CSC以及在靶向耗竭后恢复它们的机制将为有效的OSCC治疗建立一个新的概念框架。我们的初步工作已经分离出一个耐药的慢循环JARID 1B-hi细胞亚群，作为OSCC中CSC群体的候选者。JARID 1B是一种组蛋白脱甲基酶，其表达通过其他癌症类型中的功能标准识别CSC，基于其介导进入干细胞样表观遗传状态的能力，显示出作为可推广的CSC标记物的前景。JARID 1B-hi细胞中PI 3-激酶（PI 3 K）通路的过度活化使其对PI 3 K靶向药物的消耗敏感。我们的工作假设是，耗尽的JARID 1B-hi CSC池可以由具有高生长潜力和耐药性的静止“G 0样”细胞群体补充。虽然缺乏在JARID 1B-hi细胞中观察到的干细胞标志物和PI 3 K途径活性，但G 0样细胞确实显示出显著的Notch途径活化，这与CSC群体扩增和增加的PI 3 K/AKT信号传导有关。为了解释这些发现，我们的总体假设是，增殖的OSCC细胞进入静止的G 0样状态，通过提供JARID 1B-hi细胞的直接前体，产生了一个水库，以防止CSC永久耗竭。为了检验这一假设，我们将首先使用常规CSC标准检验JARID 1B-hi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 1B-hi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 1B-hi组分。其他研究将确定G 0样细胞在维持OSCC中JARID 1B-hi群体中的确切作用（目的2）。在这里，我们测试Notch介导的非CSC进入静止的G 0样状态是否形成JARID 1B-hi细胞的直接前体，从而为CSC再增殖提供了一个储库。这些概念的验证将建立新的模型系统，以剖析细胞状态转变的机制，防止治疗期间持久的口服CSC消耗。在这样做的过程中，我们的工作也将促进翻译研究，以共同靶向两种不同的肿瘤细胞表型，通过Notch和PI 3 K途径协同维持OSCC生长。