Tissue Damage-Driven Squamous Cell Carcinoma

组织损伤驱动的鳞状细胞癌

• 批准号: 10544343
• 负责人: Andrew South
• 金额: $ 34.97万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544343
• 关键词: Acids; Address; Age; Alcohol consumption; Anatomy; Automobile Driving; Biochemical; Biological Assay; Biological Availability; CDKN2A gene; Cell Separation; Cell secretion; Cells; Cervix Uteri; Cessation of life; Chronic; Clinical Markers; Collagen; Cytidine Deaminase; Data; Development; Disease model; Elements; Environment; Enzymes; Epidermolysis Bullosa Dystrophica; Epithelium; Esophagus; Event; Extracapsular; Extracellular Matrix; Extracellular Matrix Proteins; Family; Fibroblasts; Fibrosis; Gene Expression; Gene Expression Profiling; Gene Mutation; Genes; Genetic; Genetic Skin Diseases; Genome; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human papilloma virus infection; Immune; In Vitro; Induced Mutation; Infection; Inflammation; Inflammatory; Inherited; Intervention; Invaded; Lung; Malignant Neoplasms; Mediator; Molecular; Mutagenesis; Mutation; Mutation Analysis; Neoplasm Metastasis; Oral cavity; Organism; Outcome; PIK3CG gene; Pathologic; Pathway interactions; Patients; Population; Predisposition; Prevention; Process; Prognosis; Proliferating; Recurrent tumor; Regulation; Reporting; Research; Risk Factors; Role; Signal Transduction; Site; Skin; Somatic Mutation; Squamous cell carcinoma; Stimulus; TP53 gene; Testing; Therapeutic Intervention; Thrombospondin 1; Tissues; Tobacco use; Transforming Growth Factor beta; Transgenic Animals; Transgenic Mice; Tumor Cell Invasion; Tumor Promotion; Urethra; Viral; Vulva; activation-induced cytidine deaminase; advanced disease; apolipoprotein B mRNA editing enzyme; carcinogenesis; chronic wound; clinically relevant; cytokine; environmental tobacco smoke exposure; epithelial to mesenchymal transition; experimental study; improved; in vivo; inhibitor; keratinocyte; lymph nodes; microbial; mortality; mouse model; mutation assay; novel; permissiveness; polypeptide; pre-clinical; premalignant; prevent; response; single-cell RNA sequencing; skin squamous cell carcinoma; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis

Squamous cell carcinoma (SCC) is responsible for ~10% of total cancer mortality worldwide. SCC prognosis is context-dependent and does not seem to be determined by driver gene somatic mutations, which are similar across different body sites and pathological grades. Our study of SCC arising in the rare genetic skin disease Recessive Dystrophic Epidermolysis Bullosa (RDEB) has identified genetic similarities between this deadly, tissue damage-driven cancer, and a related cancer arising in the oral cavity, termed head and neck SCC (HNSCC). Our unpublished research into HNSCC has demonstrated that this similarity extends beyond genetics and has identified the composition of the extracellular matrix (ECM) within the tumor microenvironment as a potential predictor of poor outcome. Our current proposal leverages the similarities between RDEB and certain sub-types of HNSCC to explore initiation and progression events that are likely driven by different environmental stimuli but which result in the same outcome; SCC with poor prognosis. In RDEB, ~90% of patients develop cutaneous SCC by age 55 and 5-year survival is close to 0%. SCC in the skin of RDEB patients arise within chronic wounds, an environment quite different to most head and neck cancers. Nevertheless, analysis of mutations in these tumors suggests that similar mechanisms are driving tumor initiation, and analysis of gene expression and ECM proteins suggests that similar mechanisms also drive tumor progression. We have developed a novel assay of mutation in cultured keratinocytes which will determine the extent of existing mutation in single cells isolated from peri-tumoral, normal-appearing tissue, a tissue region that is prone to cancer development (a phenomenon known as ‘field cancerization’). Using this approach, we will also determine the relationship between elements associated with risk factors in HNSCC, and mutagenesis driven by endogenous deaminases of the AID (activation-induced cytidine deaminase) and APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide) family, which have been shown to be active in all SCC genomes. To address the role of ECM in progression of SCC, we will utilize a novel assay of tissue fibrosis that recapitulates the continual collagen remodeling observed in SCC fibroblasts (in both RDEB and HNSCC) when compared with normal fibroblasts isolated from the same patient which do not exhibit such collagen remodeling. We will interrogate the role of thrombospondin-1 (TSP1) in driving tumor cell invasion through two separate but related mechanisms, activation of transforming growth factor-beta signaling and regulation of ECM secretion. In parallel, we will determine the timing of mutational processes resulting from tissue damage by assessing mutation acquisition in APOBEC transgenic animals. Importantly, these studies will also enable us to evaluate APOBEC inhibition as a potential preventative or treatment intervention for SCC in a pre-clinical setting. Together, our integrated in vitro and in vivo studies will provide the rationale and platform to develop clinically relevant strategies for improved SCC treatment and prevention.

鳞状细胞癌（SCC）占全球癌症死亡率的约10%。SCC预后是 背景依赖性，似乎不是由驱动基因体细胞突变决定的， 在不同的身体部位和病理等级上。我们对罕见遗传性皮肤病引起的SCC的研究 隐性营养不良性大疱性表皮病（RDEB）已经确定了这种致命的， 组织损伤驱动的癌症，以及口腔中产生的相关癌症，称为头颈部SCC （HNSCC）。我们对HNSCC未发表的研究表明，这种相似性超出了遗传学的范围。 并已确定肿瘤微环境中细胞外基质（ECM）的组成为肿瘤微环境中的细胞外基质（ECM）。 预后不良的潜在预测因素。我们目前的建议利用了RDEB和某些 HNSCC的亚型，以探索可能由不同环境驱动的启动和进展事件 刺激，但结果相同; SCC预后不良。在RDEB中，约90%的患者发生 55岁时皮肤SCC的5年生存率接近0%。RDEB患者皮肤中的SCC出现在 慢性伤口，一个与大多数头颈癌完全不同的环境。然而，分析 这些肿瘤中的突变表明，类似的机制正在驱动肿瘤的发生，基因分析表明， 表达和ECM蛋白表明类似的机制也驱动肿瘤进展。我们有 在培养的角质形成细胞中开发了一种新的突变检测方法，该方法将确定现有突变的程度 在从肿瘤周围、外观正常的组织（一个易于发生癌症的组织区域）分离的单细胞中， 发展（一种被称为“现场癌变”的现象）。使用这种方法，我们还将确定 与HNSCC中危险因素相关的元素之间的关系，以及内源性 AID的脱氨酶（活化诱导的胞苷脱氨酶）和APOBEC（载脂蛋白B mRNA编辑 酶、催化多肽）家族，其已显示在所有SCC基因组中具有活性。解决 ECM在SCC进展中的作用，我们将利用一种新的组织纤维化检测方法， 与正常相比，在SCC成纤维细胞（RDEB和HNSCC）中观察到胶原重塑 从同一患者分离的成纤维细胞，其不表现出这种胶原重塑。我们会审问 血小板反应蛋白-1（TSP 1）通过两种独立但相关的机制在驱动肿瘤细胞侵袭中的作用， 转化生长因子β信号传导的活化和ECM分泌的调节。同时，我们将 通过评估组织损伤中的突变获得来确定由组织损伤引起的突变过程的时间， APOBEC转基因动物。重要的是，这些研究还将使我们能够评估APOBEC抑制， 在临床前环境中对SCC进行潜在的预防或治疗干预。我们的集成集成 体外和体内研究将为制定临床相关策略提供理论依据和平台， 改善SCC的治疗和预防。