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

描述（由申请人提供）：口腔鳞状细胞癌（oscc）被认为含有一类肿瘤细胞，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（CSCs）是唯一具有无限自我更新能力的细胞，因此可以分离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池，从而保持治疗相关性。准确定义能够支持口服CSC池的非CSC以及驱动这些细胞进入CSC状态的机制将为OSCC治疗建立新的范例。我们的初步工作分离出了处于“G0样”细胞状态的OSCC细胞，这些细胞先前发现具有高生长潜力、先天耐药和低水平Akt。尽管缺乏CSCs的分子标记，但这些细胞在体内表现出高致瘤性。我们的工作假设是，g0样细胞的功能特性反映了它们向CSC状态转变的能力。我们还基于高表达的JARID1B（一种已知维持其他恶性和正常干细胞表型的组蛋白去甲基化酶）在OSCCs中发现了一个假定的CSC群体。JARID1Bhigh细胞表现出功能性和分子干细胞的特征，并通过PI3K-Akt信号通路的超激活进一步与g0样亚群区分开来。为了解释这些发现，我们的总体假设是，g0样细胞中PI3K-Akt通路的再激活通过驱动它们的转变来支持它们返回CSC库

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.