Tissue Damage-Driven Squamous Cell Carcinoma

组织损伤驱动的鳞状细胞癌

• 批准号: 10322172
• 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/10322172
• 关键词: Acids; Address; Age; Alcohol consumption; Anatomy; Automobile Driving; Biochemical; Biological Assay; Biological Availability; CDKN2A gene; Cell secretion; Cells; Cervix Uteri; Cessation of life; Chronic; Clinical Markers; Collagen; Data; Deaminase; Development; Disease model; Elements; Environment; Enzymes; Epidermolysis Bullosa Dystrophica; Epithelial; 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; Infection; Inflammation; Inflammatory; Inherited; Institutes; Intervention; Lung; Malignant Neoplasms; Mediator of activation protein; Molecular; Mutagenesis; Mutation; Mutation Analysis; Neoplasm Metastasis; Oral cavity; Organism; Outcome; Pathologic; Pathway interactions; Patients; Population; Predisposition; Prevention; Process; Prognosis; Recurrence; 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; base; 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; polypeptide; pre-clinical; premalignant; prevent; response; single-cell RNA sequencing; skin squamous cell carcinoma; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; wound environment

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）负责全球癌症总死亡率约10％。 SCC预后是 依赖上下文，似乎不是由驱动基因躯体突变确定的，它们是相似的 跨不同的身体部位和病理等级。我们对罕见遗传皮肤疾病中SCC的研究 隐性营养不良的表皮溶解bullosa（RDEB）已经确定了这一致命的遗传相似之处 组织损伤驱动的癌症以及在口腔中产生的相关癌症称为头颈SCC （HNSCC）。我们对HNSCC的未发表的研究表明，这种相似性超出了遗传学 并确定肿瘤微环境中细胞外基质（ECM）的组成为一种 不良预后的潜在预测指标。我们当前的建议利用了RDEB和某些的相似之处 HNSCC的子类型探索可能由不同环境驱动的计划和进步事件 刺激，但导致相同的结果； SCC预后不良。在RDEB中，约有90％的患者发展 到55岁的皮肤SCC和5年生存率接近0％。 RDEB患者皮肤中的SCC发生在 慢性胜利，与大多数头颈部癌症完全不同的环境。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倡议，并分析基因 表达和ECM蛋白表明，相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测定法，这将决定现有突变的程度 在从肿瘤周期，正常表现组织中分离出来的单个细胞中，一个容易发生癌症的组织区域 发展（一种被称为“田间取消”的现象）。使用这种方法，我们还将确定 与HNSCC中风险因素相关的元素与内生驱动的诱变之间的关系 AID的脱氨酶（激活诱导的胞苷脱氨酶）和APOBEC（载脂蛋白B mRNA编辑 酶，催化多肽）家族，这些家族在所有SCC基因组中都活跃。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测定法，该测定法概括了延续 与正常相比 从同一患者中分离出的成纤维细胞，该患者不表现出这种胶原蛋白的重塑。我们将审问 血小板传播1（TSP1）在通过两个单独但相关的机制驱动肿瘤细胞侵袭中的作用， 转化生长因子β信号传导和ECM分泌调节的激活。同时，我们将 通过评估在 Apobec转基因动物。重要的是，这些研究还将使我们能够评估APOBEC抑制作用 SCC在临床前环境中的潜在预防或治疗干预措施。一起，我们整合了 体外和体内研究将为制定临床相关策略的基本原理和平台 改善了SCC治疗和预防。