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）： 源自皮肤和口腔的人类鳞状细胞癌（SCC）可以以类似于冬眠的惰性形式存在，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张和侵袭，但目前对其的研究还严重不足。关于惰性鳞状细胞癌持续存在的原因以及它们何时演变成攻击性形式，人们知之甚少。如果没有鳞状细胞癌惰性的分子和细胞标记，它们要么被过度治疗，从而导致发病，要么被治疗不足，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鳞状细胞癌进行比较研究的问题，我们创建了一个小鼠模型系统，其中由同一原发肿瘤发展而来的肿瘤可以进入和摆脱惰性。在该系统中，我们将人类鳞状细胞癌中两种最常见的基因改变 KrasG12D 突变体和 Smad4 缺失靶向角蛋白 K15+ 干细胞。这些小鼠迅速形成鳞状细胞癌。将这些鳞状细胞癌移植到免疫受损或免疫能力强的小鼠的皮肤后，一些鳞状细胞癌的生长与亲本肿瘤相似（非惰性），而另一些则变得惰性。当惰性鳞状细胞癌脱离惰性时，它们会迅速生长和转移。这个独特的模型系统提供匹配的惰性和非惰性 SCC 以进行纵向比较。根据我们的初步数据，我们假设：打破鳞状细胞癌惰性不仅仅是离开增殖休眠或克服微环境压力。控制肿瘤细胞自我更新和运动的内在肿瘤上皮特性和微环境影响是打破鳞状细胞癌惰性的关键因素。根据我们的初步数据，目标 1 将评估肿瘤起始细胞 (TIC) 子集的数量和特性是否影响惰性。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。目标 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效应。在这三个目标中，我们将在我们的肿瘤库中的人类鳞状细胞癌中检查负责打破小鼠鳞状细胞癌惰性的细胞过程和分子，以确定这些细胞和分子标记是否与人类鳞状细胞癌中的非或非惰性行为相关，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着加速与打破 SCC 惰性相关的标记物的识别。拟议的候选标记物功能验证将同时测试阻止 SCC 逃避的治疗策略。