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)中央癌症登记中心的数据显示，近50,000例新发癌症病例 2010年，VA系统诊断出2种癌症，前列腺癌(PCA)是最常见的 3名男性退伍军人被诊断为癌症，约12,500例，占所有癌症报告的33%。 已知吸入或摄入不完全燃烧产生的有毒空气会增加暴露。 金属离子包括铅(铅)和砷(IAS)，特别是当材料种类繁多时 6人在焚化炉中被焚烧。IAS和/或铅暴露被认为是潜在的危险因素 7对于这种癌症，但其潜在的机制在很大程度上还不清楚。在一项小型临床研究中，我们 8发现PCa患者尿中IAS和Pb值明显升高。使用新的2- 我们建立的HIT动物模型显示，暴露于IAS或铅可增加(1)Pca的风险 10活体培养；(2)前列腺上皮干细胞(PrESLCs)体外培养 11只动物在软琼脂中形成群体，这是细胞转化的标志。在这个动物模型中， 12一个月的金属治疗，然后是化学致癌物治疗，结果显著 13 IAS治疗动物前列腺癌发病率和癌前病变的增加及其趋势 在染铅动物中为14。重要的是，单细胞RNAseq分析显示铅与 15随着具有上皮性谱系标记的前ESLC亚群向间质中扩展- 16类似于致癌细胞，而IAS与一种罕见、独特的亚群的出现有关 17个致癌的PrESLCs类似于“癌症”干细胞。这个应用程序将测试以下假设 18种IAS和/或Pb1基因在不同亚群中不调节特定的、可能不同的信号通路 19前列腺上皮干细胞(PrESLCs)启动或增加前列腺癌发生的风险 20腺体。在前列腺癌发生和退伍军人中，这是一个未经验证的假设。 21健康。提出了两个目标：1)确定金属处理的前列腺癌的致癌潜能。 22上皮样干细胞(PrESLCs)在活体内应用肾移植模型进行PCA形成实验。 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)有或没有化学诱导的PCA；以及2)用金属特异性鉴定干细胞 25个转录签名。我们将使用单细胞RNA测序和可视化信息学 26以确定表征稀有金属诱导亚群的独特基因特征 27个PrESLCs群体中的癌症干细胞。我们的目标是应用这些基因签名来丰富 对28个稀有亚群进行流式细胞仪检测，并评价其致癌潜能。我们还将利用 29癌症基因组图谱PCA数据和其他在线数据库，以实现准确的分类 30种主要的、罕见的和不同亚型的PrESLC，以获得对金属致癌的见解。 31拟议工作的结论可能涉及与职业和职位有关的问题-- 32部署暴露并扩展我们在干细胞生物学方面的知识。对……的潜在影响 33退伍军人保健：成功完成这些研究可能会导致 34制定新的前列腺癌预防和治疗战略。减少不必要开支的计划 35应将暴露于这些金属离子作为预防前列腺癌的有效策略。 针对特定干细胞亚群的36种药物可用作治疗方案 37防止早期前列腺癌的发展和进展。当应用于退伍军人时，结果是 这项研究可能会拯救人类的生命，改善退伍军人的健康，并减少 39退伍军人中的残疾人数。