The Role of Dermal Fibroblasts in Skin Cancer

真皮成纤维细胞在皮肤癌中的作用

• 批准号: 10549747
• 负责人: Lindsey Nicole Seldin
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549747
• 关键词: 3-Dimensional; Ablation; Address; Aging; Award; Basal cell carcinoma; Behavior; Biological Assay; Burn injury; CRISPR/Cas technology; Cancer Burden; Carcinoma; Cells; Characteristics; Chemicals; Coculture Techniques; Coupled; Cutaneous; Cytometry; DNA Damage; Data; Dermal; Development; Disease; Environment; Environmental Exposure; Epidermis; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Exhibits; Exposure to; Failure; Fibroblasts; Fluorescence-Activated Cell Sorting; Foundations; Funding; Gene Expression; Gene Expression Profile; General Population; Goals; Growth; Health; Health Care Costs; Healthcare; Heterogeneity; Human; Hyperplasia; Image; Individual; Inflammasome; Inflammatory; Institution; Interleukin-1 beta; Maintenance; Malignant Neoplasms; Medical; Mutagens; NOD/SCID mouse; Neoplasms; Normal Cell; Organoids; Outcome; Pathogenesis; Patients; Phase; Prevalence; Process; Proliferating; Proteins; Proteomics; Quality of life; Radiation; Research; Research Proposals; Role; Sampling; Secure; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinoma; Source; Specific qualifier value; Specimen; Squamous cell carcinoma; Technical Expertise; Testing; Therapeutic; Time; Tissues; Toxic Environmental Substances; Training; Transcript; Transgenic Mice; Transplantation; Treatment Cost; Ultraviolet Rays; Veterans; Vietnam; Work; World War II; Xenograft procedure; active duty; agent orange; cancer prevention; cancer therapy; cancer type; career development; cell behavior; genetic signature; global health; improved; in vivo; inhibitor; insight; intravital imaging; knockout gene; military veteran; mouse model; novel; novel therapeutics; patient derived xenograft model; pharmacologic; prevent; programs; protein expression; repaired; response; single cell analysis; single cell technology; single-cell RNA sequencing; skill acquisition; skin disorder; targeted treatment; tumor; tumor progression; tumorigenesis; tumorigenic; wound

Basal cell carcinoma (BCC) is the most commonly occurring cancer in humans, and is particularly prevalent in the Veteran population. BCC is driven by DNA damage to the interfollicular epidermis, the body’s outermost protective barrier. Preliminary studies demonstrate that DNA damage activates inflammasome signaling in dermal fibroblasts, which enhances epithelial cell proliferation and plasticity in wild-type interfollicular epidermis, characteristics that are associated with tumorigenesis. Strikingly, however, the role of dermal fibroblasts in cutaneous skin cancer development has not been adequately addressed. Cancer-associated fibroblasts (CAFs) are predominant in tumor stroma, and have been proposed to drive the progression of many epithelial cancers, including BCC. However, the direct role of CAFs in cutaneous skin cancer progression is currently unknown. The primary goal of this CDA-2 research proposal is to test the hypothesis that inflammasome signaling from dermal CAFs promotes BCC development. This research will be the first to deeply characterize 1) epidermal and dermal live cell dynamics during BCC formation, 2) the role of CAFs in BCC development, 3) CAF necessity and sufficiency for skin cancer progression, 4) CAF signaling changes during skin tumorigenesis, and 5) the impact of specific CAF signaling subpopulations on skin cancer cell behaviors. Transgenic mouse models, live intravital imaging, patient-derived xenografts, 3D organotypic co- culture, as well as single cell analyses of primary skin cancer tissue from Veteran patients will be employed to investigate these research aims. In addition, this work will take place in a highly collaborative, supportive and rigorous research environment, and will be accompanied by both technical training and formal coursework in cancer mouse models, ex vivo organoids, CRISPR/Cas9 technology, mass cytometry, and single cell RNA sequencing. The data generated in the CDA-2 training phase, coupled with the extensive technical expertise and career development skills that will be attained, will provide a strong foundation for the long-term goals of securing VA MERIT award funding and establishing a successful independent research program at a VA- affiliated institution. The broad objective of the proposed research is to significantly improve Veteran healthcare by informing the development of targeted therapies to effectively treat and prevent cutaneous skin cancer. Additionally, this research may provide important insights into therapeutic approaches for treating other epithelial cancers as well as inflammatory skin disorders that are also common among Veterans.

基底细胞癌（BCC）是人类最常见的癌症，尤其常见于 退伍军人群体的 BCC 是由滤泡间表皮（身体最外层）的 DNA 损伤引起的。 初步研究表明，DNA 损伤会激活炎症小体信号传导。 真皮成纤维细胞，增强野生型毛囊间的上皮细胞增殖和可塑性 然而，表皮的特征与肿瘤发生相关，值得注意的是真皮的作用。 成纤维细胞在皮肤皮肤癌发展中的作用尚未得到充分解决。 成纤维细胞（CAF）在肿瘤基质中占主导地位，并被认为可以驱动许多疾病的进展 上皮癌，包括基底细胞癌 (BCC) 然而，CAF 在皮肤皮肤癌进展中的直接作用是 目前未知。该 CDA-2 研究计划的主要目标是检验以下假设： 来自真皮 CAF 的炎症小体信号传导促进 BCC 的发展。 深入表征 1) BCC 形成过程中的表皮和真皮活细胞动力学，2) CAF 在 BCC 发展，3) CAF 对皮肤癌进展的必要性和充分性，4) CAF 信号变化 皮肤肿瘤发生过程中，5) 特定 CAF 信号亚群对皮肤癌细胞的影响 转基因小鼠模型、活体活体成像、患者来源的异种移植物、3D 器官型共体。 培养以及来自退伍军人患者的原发性皮肤癌组织的单细胞分析将用于 此外，这项工作将在高度协作、支持和支持的情况下进行。 严格的研究环境，并将伴随技术培训和正式课程 癌症小鼠模型、离体类器官、CRISPR/Cas9 技术、质谱流式分析和单细胞 RNA CDA-2 训练阶段生成的数据以及广泛的技术专业知识。 将获得的职业发展技能将为实现长期目标奠定坚实的基础 获得 VA MERIT 奖励资金并在 VA- 建立成功的独立研究项目 拟议研究的广泛目标是显着改善退伍军人医疗保健。 通过告知有效治疗和预防皮肤癌的靶向疗法的开发。 此外，这项研究可能为治疗其他疾病的治疗方法提供重要见解。 上皮癌以及退伍军人中也常见的炎症性皮肤病。