Mechanisms and Therapeutic Targets of SCC Metastasis

SCC转移的机制和治疗靶点

基本信息

批准号：
10731726
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
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-10-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731726
关键词：
Acceleration Affect Biological Models Blood Vessels Cause of Death Cell Line Cell Lineage Cells Cessation of life Clinic Coculture Techniques Data Disseminated Malignant Neoplasm Distant Metastasis Dyes Exclusion 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 Invaded KRASG12D Keratin Link Lung Malignant Epithelial Cell Malignant Neoplasms Metastatic Neoplasm to Lymph Nodes Metastatic Neoplasm to the Lung Metastatic Squamous Cell Carcinoma Modeling Molecular Monitor Mus Mutation Myeloid Cells Neoplasm Metastasis Neurons Oral cavity Organ Outcome PI3 gene PIK3CG gene Pathologic Patients Population Process Prognostic Marker Property Protein Array Protein Secretion Route Side Site Skin Specimen Squamous Cell Lung Carcinoma Squamous cell carcinoma Stratified Epithelium T-Lymphocyte TP53 gene Testing Therapeutic Intervention Tobacco-Associated Carcinogen Tongue Transplantation Travel Veterans biomarker identification 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 pharmacologic 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

项目摘要

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.

方形细胞癌（SCC）来自分层上皮，这是老兵最相关的器官人口是皮肤和口腔，高暴露于紫外线辐射和烟草癌使得总和高风险的SCC大大高于平民。 SCC最糟糕的结果是死亡通过转移，最常见于肺部。 SCC死亡超过黑色素瘤死亡，原因很高 SCC案例数。缺乏赞助的SCC肺转移模型阻碍了对 SCC肺转移机制和治疗靶标。我们开发了几种基因工程在人SCC中经常发现的靶向驱动突变的小鼠模型与角蛋白K15+干细胞。这些模型发展具有不同频率的赞助肺SCC转移。与他们的派生细胞一起线条是研究不同免疫肿瘤中SCC肺转移机制的独特工具微环境（TME）。我们已经表明，癌症干细胞的亚群（CSC），即Hoechst 染料不包括侧群（SP），具有转移的能力，表明CSC特性决定了肺转移路线。我们的初步数据表明，癌症相关的成纤维细胞（CAF）来自转移性SCC在体内增强了CSC膨胀和体外侵袭，并播种到体内肺。此外，CAFS 在细胞外基质（ECM）蛋白的基因表达中经历独特的变化，以及候选标记的标记 SCC CAF与其他转移性癌症不同。最后，靶向髓样细胞减少SCC 转移。综上所述，我们假设CSC特性使它们易流行。并在肺中生存。此外，SCC-CAF串扰还具有局部和全身效应，准备转移性TME和前迁移（转移之前）/转移性（SCC细胞播种后）生态位。使用我们的小鼠模型以及患者的SCC标本，拟议的研究将确定预后标记和高风险转移性SCC的治疗靶标并开发介入的疗法将被带入诊所在不久的将来。 AIM 1将评估与多能CSC特性相关的分子是否有贡献 CSC入侵和对血管的侵入。 AIM 2将确定转移性SCC特异性CAF ECM 信号和分子标记，增强转移性CSC特性。 AIM 3将确定系统性效果 CAF-SCC相互作用，这些相互作用在原发性SCC和中转移/转移性小众中建立转移性TME 在肺部。我们独特的鼠标模型系统和跨物种与人类SCC的比较，多个高吞吐量测定和创新方法将显着加速SCC转移的发现机制和简单测试治疗干预措施。