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）起源于分层上皮，这是退伍军人中最相关的器官部位