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) 约占全球癌症死亡率的 10%。 依赖于环境，并且似乎不是由驱动基因体细胞突变决定的，这与 我们对罕见遗传性皮肤病中出现的鳞状细胞癌的研究。 隐性营养不良性大疱性表皮松解症 (RDEB) 已发现这种致命的、 组织损伤驱动的癌症，以及口腔中出现的相关癌症，称为头颈鳞状细胞癌 （HNSCC）。我们未发表的 HNSCC 研究表明，这种相似性超出了遗传学的范围。 并确定了肿瘤微环境中细胞外基质（ECM）的组成 我们当前的提议利用了 RDEB 和某些特定结果之间的相似性。 HNSCC 的亚型，以探索可能由不同环境驱动的起始和进展事件 刺激但导致相同的结果；在 RDEB 中，约 90% 的患者会出现预后不良的 SCC。 皮肤鳞状细胞癌在 55 岁时出现的 RDEB 患者的皮肤鳞状细胞癌的 5 年生存率接近 0%。 然而，慢性伤口的环境与大多数头颈癌截然不同。 这些肿瘤的突变表明类似的机制正在驱动肿瘤的发生，并且对基因的分析 表达和 ECM 蛋白表明类似的机制也驱动肿瘤进展。 开发了一种新的培养角质形成细胞突变检测方法，可确定现有突变的程度 从肿瘤周围、外观正常的组织（易患癌症的组织区域）中分离出的单细胞中 使用这种方法，我们还将确定发展（一种称为“现场癌化”的现象）。 HNSCC 危险因素相关元件与内源性诱变之间的关系 AID（激活诱导胞苷脱氨酶）和 APOBEC（载脂蛋白 B mRNA 编辑）的脱氨酶 酶（催化多肽）家族，已被证明在所有 SCC 基因组中都有活性。 为了了解 ECM 在 SCC 进展中的作用，我们将利用一种新的组织纤维化方法来概括持续的 与正常细胞相比，在 SCC 成纤维细胞（RDEB 和 HNSCC）中观察到胶原重塑 从同一患者中分离出的成纤维细胞不表现出这种胶原蛋白重塑，我们将对其进行询问。 血小板反应蛋白-1 (TSP1) 通过两种独立但相关的机制驱动肿瘤细胞侵袭， 同时，我们将激活转化生长因子-β 信号传导和调节 ECM 分泌。 通过评估突变获得来确定组织损伤引起的突变过程的时间 重要的是，这些研究还将使我们能够评估 APOBEC 抑制作用。 我们将在临床前环境中对鳞状细胞癌进行潜在的预防或治疗干预。 体外和体内研究将为开发临床相关策略提供理论基础和平台 改善 SCC 的治疗和预防。