Metal-induced cell-level changes in prostate epithelium and cancer risk

金属诱导的前列腺上皮细胞水平变化和癌症风险

• 批准号: 10664831
• 负责人: Shuk-Mei Ho
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664831
• 关键词: Address; Adult; Agar; Air; Animal Model; Animals; Apoptotic; Applications Grants; Arsenic; Biological Assay; Cancer Patient; Carcinogens; Carcinoma; Categories; Cell Lineage; Cell Separation; Cells; Chemicals; Classification; Clinic; Clinical Research; DNA Damage; Data; Databases; Development; Diagnosis; Dose; Drug Targeting; Environment; Environmental Exposure; Environmental and Occupational Exposure; Epithelial Cells; Epithelium; Exposure to; Foundations; Future; Gene Expression; Genomic Instability; Gland; Goals; Health; Healthcare; Human; Immune; Immunocompetence; Incidence; Informatics; Ingestion; Inhalation; International Agencies; Ions; Kidney Transplantation; Knowledge; Lead; Lead levels; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Metal Carcinogenesis; Metal exposure; Metals; Molecular; Molecular Profiling; Mus; Occupational; Occupations; Oncogenic; Phenotype; Physiological; Pilot Projects; Population; Predisposition; Probability; Prostate; Public Domains; Reporting; Resistance; Risk; Risk Assessment; Risk Factors; Signal Pathway; Survival Analysis; System; Testing; The Cancer Genome Atlas; Therapeutic; United States; United States Department of Veterans Affairs; Universities; Urine; Urology; Veterans; Visit; Visualization; Work; anticancer research; cancer diagnosis; cancer risk; cancer stem cell; carcinogenesis; carcinogenicity; cell transformation; chemical carcinogen; clinically significant; cohort; design; disability; disorder prevention; drinking water; epithelial stem cell; genetic signature; hazard; human disease; improved; in vivo; in vivo Model; insight; lead exposure; male; metaplastic cell transformation; military service; military veteran; mouse model; neoplasm registry; novel; novel strategies; precision genomic medicine; precision medicine; premalignant; prevent; prostate cancer model; prostate cancer prevention; prostate cancer risk; prostate carcinogenesis; single-cell RNA sequencing; specific biomarkers; stem cell biology; stem cell biomarkers; stem cell division; stem cell niche; stem cell population; stem cells; stem-like cell; stemness; transcriptome; transcriptomics; trend; understudied cancer

1 Data in the Veterans Affairs (VA) Central Cancer Registry showed nearly 50,000 new cases of 2 cancers were diagnosed in the VA system in 2010, and prostate cancer (PCa) is the most frequently 3 diagnosed cancer among male veterans, with ~12,500 cases or 33% of all cancers reported. 4 Inhalation or ingestion of toxic air from incomplete combustion are known to increase exposure 5 to metal ion including lead (Pb) and arsenic (iAs), especially when a great variety of materials 6 were being burnt in burnpit. iAs and/or Pb exposure have been considered as potential risk factors 7 for this cancer, but the underlying mechanism is largely undefined. In a small clinical study, we 8 found that iAs and Pb levels were significantly higher in the urine of PCa patients. Using a new 2- 9 hit animal model we established, exposure to iAs or Pb was showed to increase (1) PCa risk in 10 vivo, and (2) the ability of prostate epithelial stem-like cells (PrESLCs) isolated from treated 11 animals to form colonies in soft agar, a hallmark of cellular transformation. In this animal model, 12 a 1-month metal treatment followed by chemical carcinogen treatment, resulted in significant 13 increases in PCa incidence and pre-cancerous lesions in iAs-treated animal and trends of increases 14 in Pb-treated animals. Importantly, single-cell RNAseq analyses revealed that Pb was associated 15 with the expansion of a subpopulation of PrESLCs with epithelial lineage markers into stroma- 16 like oncogenic cells, while iAs was associated with the emergence of a rare, unique subpopulation 17 of oncogenic PrESLCs similar to “cancer” stem cells. This application will test the hypothesis that 18 iAs and/or Pb dysregulate specific, and likely different, signaling pathways in subpopulations of 19 prostate epithelial stem-like cells (PrESLCs) to initiate or increase the risk of carcinogenesis in the 20 gland. This is an untested hypothesis in the field of prostate carcinogenesis and in military veterans’ 21 health. Two Aims were proposed: 1) Determine the carcinogenic potential of metal-treated prostate 22 epithelial stem-like cells (PrESLCs) in vivo using a renal grafting model of PCa formation assay. 23 We will evaluate the effects of metals on to form PCa in vivo in immune-deficient host mice, either 24 with or without chemical induction of PCa; and 2) Characterize stem-like cells with metal-specific 25 transcriptomic signatures. We will use single-cell RNA sequencing and visualization informatics 26 to identify the unique gene signatures that characterize rare subpopulations of metal-induced 27 cancer stem cells within the PrESLCs population. We aim to apply these gene signatures to enrich 28 rare subpopulations by FACS and evaluate their carcinogenic potential. We will also leverage The 29 Cancer Genome Atlas PCa data and other online databases to enable accurate classification of 30 major, rare, and heterogeneous subtypes of PrESLCs to gain insights in metal carcinogenesis. 31 Findings from the proposed work may address questions related to occupational and post- 32 deployment exposure and expand our knowledge on stem cell biology. Potential Impact on 33 Veterans Health Care: Successful completion of these studies can potentially lead to the 34 development of new PCa prevention and therapeutic strategies. Plans to reduce unnecessary 35 exposure to those metal ions should be implemented as effective strategy for PCa prevention. 36 Drugs targeting to specific subpopulation of stem cells could be used as therapeutic options to 37 prevent early PCa development as well as progression. When applied to veterans, the results of 38 this study may allow saving human lives, improving the health of veterans, and decreasing the 39 number of disabilities in the veteran population.

1 退伍军人事务部 (VA) 中央癌症登记处的数据显示，近 50,000 个新病例 2010 年 VA 系统诊断出 2 种癌症，其中前列腺癌 (PCa) 是最常见的癌症 3 在男性退伍军人中诊断出癌症，约有 12,500 例病例，占所有癌症报告的 33%。 4 已知吸入或摄入不完全燃烧产生的有毒空气会增加接触风险 5 金属离子，包括铅 (Pb) 和砷 (iAs)，特别是当材料种类繁多时 6 人在烧坑中被烧伤 砷和/或铅暴露被认为是潜在的危险因素。 7 对于这种癌症，但在一项小型临床研究中，其潜在机制很大程度上尚未确定。 8 使用新的 2- 发现 PCa 患者尿液中的 iAs 和 Pb 水平显着升高。 我们建立的 9 种动物模型中，暴露于 iAs 或 Pb 被证明会增加 (1) PCa 风险 10 体内，以及（2）从治疗中分离的前列腺上皮干细胞（PrESLC）的能力 11 只动物在软琼脂中形成菌落，这是细胞转化的标志。 12 为期 1 个月的金属处理，随后进行化学致癌物处理，结果显着 13 iAs 治疗动物 PCa 发病率和癌前病变增加以及增加趋势 14 在 Pb 处理的动物中，重要的是，单细胞 RNAseq 分析表明 Pb 与之相关。 15 随着具有上皮谱系标记的 PrESLC 亚群扩展到基质中 16 类似致癌细胞，而 iAs 与罕见、独特亚群的出现有关 17 种与“癌症”干细胞相似的致癌 PrESLC 该应用将检验以下假设： 18 iAs 和/或 Pb 失调亚群中特定且可能不同的信号传导途径 19 前列腺上皮干细胞样细胞 (PrESLC) 启动或增加致癌风险 20 腺体，这是前列腺癌发生领域和退伍军人领域未经检验的假设。 21 健康 提出了两个目标： 1) 确定金属处理的前列腺的致癌潜力。 22 体内上皮干细胞样细胞 (PrESLC) 使用肾移植模型进行 PCa 形成测定。 23 我们将评估金属对免疫缺陷宿主小鼠体内形成 PCa 的影响，或者 24 有或没有化学诱导 PCa；以及 2) 表征具有金属特异性的干细胞样细胞 25 个转录组特征我们将使用单细胞 RNA 测序和可视化信息学。 26 确定表征金属诱导的稀有亚群的独特基因特征 我们的目标是应用这些基因特征来丰富 PrESLC 群体中的 27 种癌症干细胞。 通过 FACS 分析 28 个罕见亚群并评估其致癌潜力。 29 癌症基因组图谱 PCa 数据和其他在线数据库，以实现准确分类 PrESLC 的 30 种主要、罕见和异质亚型，以深入了解金属致癌作用。 31 拟议工作的结果可能会解决与职业和岗位相关的问题。 32 部署暴露并扩展我们对干细胞生物学的潜在影响。 33 退伍军人医疗保健：成功完成这些研究可能会导致 34 制定新的PCa预防和治疗策略，以减少不必要的治疗。 35 应将接触这些金属离子作为预防 PCa 的有效策略。 36 针对特定干细胞亚群的药物可用作治疗选择 37 预防 PCa 的早期发展和进展 当应用于退伍军人时，结果如下。 38 这项研究可能有助于拯救人类生命、改善退伍军人的健康并减少 退伍军人中残疾人数39人。