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: 10368503
• 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/10368503
• 关键词: 3-Dimensional; 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; Epithelial Cell Proliferation; Epithelial Cells; Exhibits; Exposure to; Failure; Fibroblasts; Fluorescence-Activated Cell Sorting; Foundations; Funding; Gene Expression; Gene Expression Profile; 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; Pharmacology; Phase; Prevalence; Process; Proteins; Proteomics; Quality of life; Radiation; Research; Research Proposals; Role; Sampling; Secure; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinoma; Source; 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; 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）是人类中最常见的癌症，在 退伍军人人口。 BCC受到DNA损坏对裂纹表皮的损害，该表皮是人体最外面的 保护性障碍。初步研究表明，DNA损伤激活了炎性体信号传导 真皮成纤维细胞，可增强野生型界面的上皮细胞增殖和可塑性 表皮，与肿瘤发生相关的特征。然而，令人惊讶的是真皮的作用 皮肤癌发育中的成纤维细胞尚未得到充分解决。癌症相关 成纤维细胞（CAFS）主要在肿瘤基质中，并被提议驱动许多 上皮癌，包括BCC。但是，CAF在皮肤皮肤癌进展中的直接作用是 目前未知。该CDA-2研究建议的主要目标是检验以下假设。 皮肤CAFS的炎性体信号传导促进了BCC的发展。这项研究将是第一个 深层表征1）BCC形成期间表皮和真皮活细胞动力学，2）CAF在 BCC开发，3）CAF必要的和对皮肤癌进展的充分性，4）CAF信号变化 在皮肤肿瘤发生期间和5）特定CAF信号亚群对皮肤癌细胞的影响 行为。转基因小鼠模型，活体内成像，患者衍生的Xenographictics，3D有机共同 培养，以及来自老将患者的原发性皮肤癌组织的单细胞分析将被聘为 研究这些研究目的。此外，这项工作将在高度协作，支持性和 严格的研究环境，将通过技术培训和正式课程来完成 癌症小鼠模型，离体器官，CRISPR/CAS9技术，质量细胞术和单细胞RNA 测序。在CDA-2训练阶段产生的数据，再加上广泛的技术专长 以及将附加的职业发展技能，将为长期目标提供坚实的基础 确保VA绩效奖励资金并在VA-建立成功的独立研究计划 会员机构。拟议研究的广泛目标是显着改善资深医疗保健 通过通知有效治疗和预防皮肤癌的靶向疗法的发展。 此外，这项研究可能会为治疗其他治疗方法提供重要的见解 在退伍军人中也很常见的上皮癌以及炎症性皮肤疾病。