Mechanisms and Therapeutic Targets of SCC Metastasis

SCC转移的机制和治疗靶点

• 批准号: 10356069
• 负责人: Xiao-Jing Wang
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356069
• 关键词: Affect; Biological Models; Blood Vessels; Cause of Death; Cell Line; Cell Lineage; Cells; Cessation of life; Clinic; Data; Disseminated Malignant Neoplasm; Distant Metastasis; Dyes; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Frequencies; Future; Gene Expression; Genetic; Genetically Engineered Mouse; Head and neck structure; Hematopoietic; Human; Image; Immunocompetent; In Vitro; KRASG12D; Keratin; Link; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Metastatic Neoplasm to Lymph Nodes; Metastatic Neoplasm to the Lung; Metastatic Squamous Cell Carcinoma; Metastatic to; Modeling; Molecular; Monitor; Mus; Mutation; Myeloid Cells; Neoplasm Metastasis; Neurons; Oral cavity; Organ; Outcome; PI3 gene; Pathologic; Patients; Pharmacology; Population; Process; Prognostic Marker; Property; Protein Array; Proteins; Route; Site; Skin; Specimen; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; Stratified Epithelium; T-Lymphocyte; TP53 gene; Testing; Therapeutic Intervention; Time; Tobacco-Associated Carcinogen; Tongue; Transplantation; Travel; Veterans; base; cancer stem cell; cancer type; candidate marker; design; driver mutation; high risk; high throughput screening; in vivo; inhibitor; innovation; knock-down; liquid biopsy; melanoma; migration; military veteran; molecular marker; mouse model; nano-string; prognosis biomarker; protein biomarkers; restoration; single-cell RNA sequencing; skin squamous cell carcinoma; spectrograph; stem cell expansion; stem cells; therapeutic evaluation; therapeutic target; tool; tumor microenvironment; tumor-immune system interactions; two-photon; ultraviolet irradiation

Squamous cell carcinomas (SCCs) arise from stratified epithelia, the most relevant organ sites in the veteran population are the skin and oral cavity where high exposure to UV irradiation and tobacco carcinogens make the total and high-risk SCCs significantly higher than the civilian population. SCC’s worst outcome is death through metastasis, most commonly in the lung. SCC deaths exceed melanoma deaths due to the high number of SCC cases. The lack of spontaneous SCC lung metastasis models has hindered identification of SCC lung metastasis mechanisms and therapeutic targets. We developed several genetically engineered mouse models that target driver mutations frequently found in human SCCs to keratin K15+ stem cells. These models develop spontaneous lung SCC metastasis with different frequencies. Together with their derived cell lines, they are unique tools to study mechanisms of SCC lung metastasis in different immune tumor microenvironments (TME). We have shown that a subpopulation of cancer stem cells (CSCs), i.e., the Hoechst dye excluding side population (SP), have the ability to metastasize, suggesting that CSC properties dictate the lung metastasis route. Our preliminary data revealed that cancer associated fibroblasts (CAFs) derived from metastatic SCCs enhanced CSC expansion and invasion in vitro and seeding to the lung in vivo. Further, CAFs undergo unique changes in gene expression of extracellular matrix (ECM) proteins, and candidate markers for SCC CAFs are distinctive from other metastatic cancers. Lastly, targeting myeloid cells reduced SCC metastasis. Taken together, we hypothesize that CSC properties predispose them to travel via blood vessels and survive in the lung. Additionally, SCC-CAF crosstalk has local and systemic effects preparing the metastatic TME and premetastatic (prior to metastasis)/metastatic (after SCC cell seeding) niche. Using our mouse models as well as patients’ SCC specimens, the proposed studies will identify prognostic markers and therapeutic targets for high risk metastatic SCCs and develop interventional therapies that will be brought into clinic in the near future. Aim 1 will assess if molecules associated with multipotent CSC properties contribute to CSCs invasion and intravasation to blood vessels. Aim 2 will identify metastatic SCC-specific CAF ECM signatures and molecular markers that enhance metastatic CSC properties. Aim 3 will identify systemic effects of CAF-SCC interactions that establish a metastatic TME in primary SCC and pre-metastatic/metastatic niche in the lung. Our unique mouse model systems and cross-species comparisons with human SCCs, multiple high throughput assays and innovative approaches will significantly accelerate discovery of SCC metastasis mechanisms and simultaneously test therapeutic interventions.

鳞状细胞癌(SCCs)起源于复层上皮，这是退伍军人最相关的器官部位 人群是皮肤和口腔，在那里高暴露于紫外线辐射和烟草致癌物 总鳞癌和高危鳞癌明显高于平民百姓。SCC的最坏结果是死亡 通过转移，最常见的是在肺部。鳞癌死亡人数超过黑色素瘤死亡人数 鳞状细胞癌病例数。缺乏自发性鳞状细胞癌肺转移模型阻碍了对 鳞状细胞癌肺转移机制及治疗靶点。我们开发了几种基因工程 以人类干细胞中常见的驱动程序突变为角蛋白K15+干细胞的小鼠模型。这些 模型发生自发性肺鳞状细胞癌转移的频率不同。以及它们的派生细胞 LINES是研究不同免疫性肿瘤中SCC肺转移机制的独特工具 微环境(TME)。我们已经证明了癌症干细胞的一个亚群，即Hoechst 不包括侧集居数(SP)的染料具有转移的能力，这表明CSC的性质决定了 肺转移途径。我们的初步数据显示，癌症相关成纤维细胞(CAF)来源于 转移性SCCs在体外可促进CSC的扩增和侵袭，在体内可促进CSC在肺内的种植。此外，CAF 经历细胞外基质(ECM)蛋白基因表达的独特变化，以及候选标记 鳞状细胞癌CAF有别于其他转移性癌症。最后，以髓系细胞为靶点可降低鳞癌 转移。综上所述，我们假设CSC的特性使它们易于通过血管旅行 并在肺中存活。此外，SCC-CAF串扰具有局部和系统效应 转移性TME和转移前(转移前)/转移(SCC细胞种植后)生态位。使用我们的 小鼠模型和患者的鳞癌标本，拟议的研究将确定预后标志物和 针对高危转移性鳞状细胞癌的治疗靶点，并开发将被引入的介入治疗 在不久的将来，将会有一家诊所。Aim 1将评估与多潜能CSC特性相关的分子是否对 与CSCs侵袭和血管内渗有关。AIM 2将识别转移性鳞癌特异性CAF ECM 增强转移性CSC特性的签名和分子标记。目标3将确定系统性影响 CAF-SCC相互作用在原发鳞癌和转移前/转移生态位建立转移性TME的研究 在肺里。我们独特的小鼠模型系统和人类SCC的跨物种比较，多高 吞吐量分析和创新方法将显著加速发现鳞状细胞癌转移 并同时测试治疗干预措施。