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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.

鳞状细胞癌 (SCC) 起源于复层上皮，这是退伍军人最相关的器官部位人口是皮肤和口腔，高度暴露于紫外线照射和烟草致癌物会使 SCC 总数和高危人群明显高于平民。 SCC最坏的结果是死亡通过转移，最常见于肺部。鳞状细胞癌死亡人数超过黑色素瘤死亡人数，原因是 SCC 病例数。缺乏自发性 SCC 肺转移模型阻碍了 SCC肺转移机制和治疗靶点。我们开发了多种基因工程将人类鳞状细胞癌中常见的驱动突变靶向角蛋白 K15+ 干细胞的小鼠模型。这些模型以不同的频率发生自发性肺 SCC 转移。连同它们的衍生细胞线，它们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）。我们已经证明，癌症干细胞 (CSC) 的一个亚群，即 Hoechst 排除侧群 (SP) 的染料具有转移能力，表明 CSC 特性决定了肺转移途径。我们的初步数据显示，癌症相关成纤维细胞（CAF）源自转移性鳞状细胞癌在体外增强了鳞状细胞癌的扩张和侵袭，并在体内增强了鳞状细胞癌向肺部的种植。此外，CAF 细胞外基质（ECM）蛋白的基因表达发生独特的变化，以及候选标记物 SCC CAF 与其他转移性癌症不同。最后，靶向骨髓细胞可减少鳞状细胞癌转移。综上所述，我们假设 CSC 特性使它们易于通过血管传播并在肺中存活。此外，SCC-CAF 串扰具有局部和系统效应，可以为转移性 TME 和转移前（转移前）/转移性（SCC 细胞接种后）生态位。使用我们的小鼠模型以及患者的鳞状细胞癌标本，拟议的研究将确定预后标志物和高风险转移性鳞状细胞癌的治疗靶点并开发介入疗法，并将其引入在不久的将来的诊所。目标 1 将评估与多能 CSC 特性相关的分子是否有贡献 CSCs 侵袭和血管内渗。目标 2 将识别转移性 SCC 特异性 CAF ECM 增强转移性 CSC 特性的特征和分子标记。目标 3 将确定系统性影响 CAF-SCC 相互作用在原发性 SCC 和转移前/转移生态位中建立转移性 TME 在肺里。我们独特的小鼠模型系统以及与人类 SCC 的跨物种比较，多个高通量测定和创新方法将显着加速 SCC 转移的发现机制并同时测试治疗干预措施。