Promotion of photocarcinogenesis by the senescent field and mechanisms for field persistence

衰老场促进光致癌作用和场持久性机制

• 批准号: 10487791
• 负责人: RAYMOND L KONGER
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487791
• 关键词: Age; Area; Carcinoma; Cell Aging; Cells; Characteristics; Clonal Expansion; Complement Factor B; Cutaneous; Cyclosporine; Dermal; Development; Epithelial; Exposure to; Fibroblasts; Ganciclovir; Graft Rejection; Hemoglobin; Image; Immune; Immune system; Immunocompromised Host; Immunosuppression; Immunosuppressive Agents; Individual; Inflammatory; Isogenic transplantation; Lead; Link; Malignant Conversion; Malignant Neoplasms; Maps; Measures; Mediating; Mediator of activation protein; Mitotic; Modeling; Mus; Mutation; Organ Transplantation; Paracrine Communication; Phenotype; Play; Process; Production; Risk; Risk Factors; Role; Signal Transduction; Sirolimus; Site; Skin Cancer; Solid; Stromal Cells; Sun Exposure; Sunlight; Testing; Therapeutic immunosuppression; Thymidine Kinase; Time; Training; Transforming Growth Factor alpha; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Transplant Recipients; Transplantation; Tumor Expansion; UV Radiation Exposure; UV carcinogenesis; UV induced; UVA induced; Ultraviolet Rays; Ultraviolet Therapy; Variant; Veterans; Wild Type Mouse; angiogenesis; anti aging; cancer risk; carcinogenesis; chemokine; cytokine; differential expression; high risk; immunoregulation; immunosuppressed; in vivo; mutant; neoantigens; novel; promoter; senescence; single-cell RNA sequencing; transcriptome sequencing; tumor; tumorigenesis

Exposure to the ultraviolet (UV) rays of sunlight is the primary cause of skin cancer, which kills greater than 20,000 U.S. individuals each year. Veterans are at increased risk for skin cancer development due to increased sun exposure during training and deployment. UV exposure also causes photoaging that results in cells acquiring a post-mitotic phenotype called senescence. In addition to sun exposure, age and treatment with immunosuppressants are the most significant risk factors for skin cancer development. In this proposal, we will examine our novel 2 component cancer field model of cutaneous carcinogenesis that links photoaging and immunosuppression to skin cancer development. Historically, the cancer field refers to multifocal areas of otherwise normal epithelium that are at increased risk for cancer development. This epithelial cancer field is characterized by the stepwise accumulation of mutations that eventually lead to malignant conversion. We have shown that UV induces a multifocal dermal senescent field that is characterized by inflammatory angiogenesis that can be visualized and measured by imaging the dermal hemoglobin (Hb) content. This dermal field persists & expands following cessation of UV treatments and predicts sites of overlying epidermal clonal expansion & tumor formation. In this proposal, we propose that a dermal field also exists and that the key characteristic of this dermal field is the presence of senescent cells. These senescent cells produce and secrete specific pro-inflammatory, mitogenic and immunomodulatory mediators that we propose drive the continued development of the overlying epithelial mutant field. However, the immune system can recognize and clear senescent cells (senescence surveillance). We predict that this immune-mediated clearance acts to suppress the effects of the senescent dermal field on tumor formation. We expect that treatment with immunosuppressive drugs would promote tumorigenesis by blocking immune-mediated clearance of dermal senescent cells. Transforming growth factor beta (TGF-β) is a cytokine that is necessary for UV-induced senescence and is produced by senescent cells. This TGF-β production can in turn result in the induction of senescence in nearby cells (bystander senescence). We propose that bystander senescence, in an immunosuppressed setting, provides a self-perpetuating mechanism that drives senescent field persistence AND expansion. Finally, not all immunosuppressive agents have the same capacity to promote skin cancer development. Cyclosporine A promotes skin cancer development, TGF-β production, and induces senescence. In contrast, sirolimus has a limited effect on skin cancer risk, is known to suppresses TGF-β production, and suppresses senescent cell formation and secretory activity. In this proposal, we will determine whether the UV- induced senescent field is necessary for skin cancer development, determine whether immunosuppressive therapy promotes senescent field development and persistence, and determine whether TGF-β signaling & bystander senescence play central roles in this process. This will be done in three aims: Aim 1: Determine whether senolytic therapy inhibits photocarcinogenesis and dermal field persistence. Examine whether senolytic therapy and loss of TGF-β signaling block the ability of cyclosporine A to enhance, and sirolimus to suppress, UV-induced tumor formation. Aim 2. Use single cell RNA sequencing (scRNAseq) and dermal whole transcriptome sequencing and differential expression analysis to characterize the differences between hyperemic and non-hyperemic foci. Aim 3. Determine whether cyclosporine A suppresses senescence surveillance and promotes bystander senescence in wildtype while sirolimus acts to suppress bystander senescence. The role of TGF-β on bystander senescence will also be assessed.

暴露于阳光中的紫外线 (UV) 是导致皮肤癌的主要原因，该病可导致超过 100 人死亡 由于皮肤癌的增加，每年有 20,000 名美国退伍军人患皮肤癌的风险增加。 训练和部署期间的阳光照射也会导致细胞光老化。 除了阳光照射、年龄和治疗外，获得称为衰老的有丝分裂后表型。 免疫抑制剂是皮肤癌发展的最重要的危险因素。 检查我们新颖的皮肤癌发生的 2 成分癌症场模型，该模型将光老化和 免疫抑制对皮肤癌的发展历史上，癌症领域是指多灶性区域。 正常上皮细胞发生癌症的风险增加。 其特点是突变逐步积累，最终导致恶性转化。 已经表明，紫外线会诱导多灶性真皮衰老场，其特征是炎症 可以通过对真皮血红蛋白 (Hb) 含量进行成像来可视化和测量血管生成。 停止紫外线治疗后，真皮区域持续存在并扩大，并预测覆盖表皮的部位 克隆扩张和肿瘤形成 在这个提案中，我们提出真皮区也存在并且 该真皮区域的关键特征是存在衰老细胞，这些衰老细胞产生和。 分泌特定的促炎、促有丝分裂和免疫调节介质，我们建议这些介质驱动 然而，免疫系统可以识别上皮突变区域的持续发展。 并清除衰老细胞（衰老监视）。 我们期望抑制衰老真皮区域对肿瘤形成的影响。 免疫抑制药物会通过阻断免疫介导的真皮清除来促进肿瘤发生。 转化生长因子β (TGF-β) 是紫外线诱导所必需的细胞因子。 衰老细胞产生的这种 TGF-β 反过来又会导致诱导 附近细胞的衰老（旁观者衰老）。 免疫抑制环境，提供了一种驱动衰老场持久性的自我延续机制 最后，并非所有免疫抑制剂都具有相同的促进皮肤癌的能力。 环孢菌素 A 促进皮肤癌的发展、TGF-β 的产生并诱导衰老。 相比之下，西罗莫司对皮肤癌风险的影响有限，已知可以抑制 TGF-β 的产生，并且 抑制衰老细胞的形成和分泌活性 在本提案中，我们将确定紫外线是否会抑制衰老细胞的形成和分泌活动。 诱导衰老场对于皮肤癌的发展是必要的，确定是否需要免疫抑制 治疗促进衰老区域的发育和持久性，并确定 TGF-β 信号传导是否与 旁观者衰老在这一过程中发挥着核心作用，这将实现三个目标： 目标 1：确定 senolytic 疗法是否抑制光致癌和真皮场持久性。 检查 senolytic 疗法和 TGF-β 信号传导的丧失是否会阻碍环孢素 A 增强的能力， 和西罗莫司抑制紫外线诱导的肿瘤形成。 目标 2. 使用单细胞 RNA 测序 (scRNAseq) 和真皮全转录组测序 差异表达分析来表征充血病灶和非充血病灶之间的差异。 目标 3. 确定环孢菌素是否抑制衰老监视并促进旁观者 野生型衰老，而西罗莫司则抑制旁观者衰老。 TGF-β 对旁观者衰老的作用。 还将评估衰老情况。