Mechanisms of Breaking Indolence in Squamous Cell Carcinoma

打破鳞状细胞癌惰性的机制

• 批准号: 9137250
• 负责人: Xiao-Jing Wang
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137250
• 关键词: Affect; Apoptosis; B-Lymphocytes; Behavior; Biological Models; Cell Death; Cell physiology; Cells; Cessation of life; Comparative Study; Data; Dyes; Epithelial; Equilibrium; Experimental Models; Fibroblasts; Hibernation; Human; Immune; In Vitro; Individual; Indolent; Infiltration; Inflammatory; Keratin; Lung; Malignant Neoplasms; Mediating; Mesenchymal; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Mutation; Neoplasm Metastasis; Oral cavity; Patients; Plasma; Play; Population; Primary Neoplasm; Property; Risk; Role; Self-control as a personality trait; Side; Signal Transduction; Site; Skin; Small Interfering RNA; Squamous Cell; Squamous Differentiation; Squamous cell carcinoma; Stem cells; Stress; System; T-Lymphocyte; Testing; Therapeutic; Time; Transforming Growth Factor beta; Transplantation; Tumor Bank; Tumor Cell Invasion; Tumor Expansion; Tumor Immunity; Tumor Initiators; Tumor-Derived; Validation; angiogenesis; base; biomarker identification; cancer cell; candidate marker; candidate validation; cell growth; cell motility; chemokine; cytokine; design; in vivo; knock-down; macrophage; molecular marker; mouse model; mutant; neoplastic cell; outcome forecast; predictive marker; public health relevance; self-renewal; therapeutic evaluation; tumor

 DESCRIPTION (provided by applicant): Human squamous cell carcinomas (SCCs) arising from the skin and oral cavity can present in an indolent form, similar to hibernation, with no obvious tumor expansion or local/systemic invasion. SCC indolence, which restricts net tumor expansion and invasion at the primary site, is severely understudied. Very little is known about why indolent SCCs persist and when they evolve into an aggressive form. Without molecular and cellular markers of SCC indolence, they are either over-treated thus causing morbidity or under-treated thus resulting in increased death. To overcome the lack of matched indolent and evolved SCCs in humans for comparative studies, we created a mouse model system, in which tumors developed from the same primary tumor can enter into and break out of indolence. In this system, we targeted a KrasG12D mutant and Smad4 deletion, the two most frequent genetic alterations in human SCCs, into keratin K15+ stem cells. These mice rapidly develop SCCs. After transplanting these SCCs to the skin of immune compromised or immune competent mice, some grew similarly to parental tumors (non-indolent) while others became indolent. When indolent SCCs were out-of-indolence, they grew and metastasized rapidly. This unique model system provides matched indolent and out-of-indolence SCCs for longitudinal comparisons. Based on our preliminary data, we hypothesize: Breaking SCC indolence is not simply leaving proliferative dormancy or overcoming microenvironmental stress. Intrinsic tumor epithelial properties and microenvironmental influences that control self-renewal and motility of tumor cells are key contributors of breaking SCC indolence. Based on our preliminary data, Aim 1 will assess if the numbers and properties of a subset of tumor initiating cells (TICs) influence indolence. Aim 2 will assess if EMT-mediated TIC expansion and cell migration are sufficient to contribute to breaking indolence. Aim 3 will determine the net effect of tumor-associated macrophages and B lymphocytes on tumor indolence. In all three aims, cellular processes and molecules responsible for breaking SCC indolence in mice will be examined in human SCCs from our tumor bank to determine if these cellular and molecular markers correlate with non- or out-of-indolence behavior in human SCCs, thus predicting poor prognosis. Our unique model system, high throughput approaches and cross- species comparisons will significantly accelerate identification of markers associated with breaking SCC indolence. The proposed functional validation of candidate markers will simultaneously test therapeutic strategies to halt SCC evasion.

 描述(由申请人提供)： 人类鳞状细胞癌(SCCs)起源于皮肤和口腔，可以表现为类似冬眠的惰性形式，没有明显的肿瘤扩张或局部/全身侵袭。鳞状细胞癌的惰性限制了肿瘤在原发部位的净扩散和侵袭，但研究严重不足。对于懒惰的鳞状细胞为什么持续存在，以及它们何时演变为侵略性的形式，人们知之甚少。如果没有分子和细胞标记的鳞癌惰性，它们要么过度治疗从而导致发病率，要么治疗不足从而导致死亡增加。为了克服人类缺乏匹配的惰性和进化的干细胞进行比较研究，我们创建了一个小鼠模型系统，在这个系统中，从同一原发肿瘤发展而来的肿瘤可以进入和脱离惰性。在这个系统中，我们以KrasG12D突变和Smad4缺失为靶点，将人类SCC中最常见的两种基因改变转化为角蛋白K15+干细胞。这些小鼠迅速发展成鳞状细胞。在将这些干细胞移植到免疫功能低下或免疫能力强的小鼠的皮肤后，一些小鼠的生长类似于亲代肿瘤(非惰性)，而另一些则变得懒惰。当惰性细胞脱离惰性时，它们会迅速生长和转移。这一独特的模型系统为纵向比较提供了匹配的惰性和非惰性SCC。根据我们的初步数据，我们假设：打破SCC的惰性不仅仅是离开增殖休眠或克服微环境压力。固有的肿瘤上皮特性和控制肿瘤细胞自我更新和运动的微环境影响是打破SCC惰性的关键因素。根据我们的初步数据，目标1将评估肿瘤启动细胞(TICs)子集的数量和特性是否会影响懒惰。目标2将评估EMT介导的TIC扩张和细胞迁移是否足以有助于打破惰性。目的3将确定肿瘤相关巨噬细胞和B淋巴细胞对肿瘤惰性的净作用。在所有三个目标中，负责打破小鼠SCC惰性的细胞过程和分子将在我们的肿瘤库中的人类SCCs中进行检测，以确定这些细胞和分子标志物是否与人类SCC的无或不惰性行为相关，从而预测不良预后。我们独特的模型系统、高通量方法和跨物种比较将显著加快识别与打破SCC惰性相关的标记。拟议的候选标记物的功能验证将同时测试阻止鳞癌逃避的治疗策略。