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: 10382227
• 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/10382227
• 关键词: Address; Adult; Agar; Air; Animal Model; Animals; Apoptotic; Applications Grants; Arsenic; Biological Assay; Cancer Patient; Carcinogens; Carcinoma; Cell Lineage; Cell Separation; Cells; Chemicals; Classification; Clinic; Clinical Research; DNA Damage; Data; Databases; Development; Diagnosis; Dose; Drug Targeting; Environmental Exposure; Environmental and Occupational Exposure; Epithelial; Epithelial Cells; 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; Prostate; Public Domains; Reporting; Resistance; Risk; Risk Assessment; Risk Factors; Savings; 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; base; 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

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退伍军人事务中的1个数据（VA）中央癌症注册表显示了近50,000例新案例 2010年在VA系统中诊断了2种癌症，前列腺癌（PCA）是最常的 在男性退伍军人中被诊断出癌症，约有12,500例报告，占所有癌症的33％。 4已知吸入或摄入有毒空气不完全的组合会增加暴露 5到金属离子，包括铅（PB）和砷（IAS），尤其是当多种材料 伯恩比特有6人被烧毁。 IAS和/或PB暴露已被视为潜在的风险因素 7对于这种癌症，但基本机制在很大程度上是不确定的。在一项小型临床研究中，我们 8发现，PCA患者尿液中的IAS和PB水平明显更高。使用新的2- 9命中动物模型我们建立，暴露于IAS或PB会增加（1）PCA风险 10体内和（2）从处理的前列腺上皮样细胞（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。在这个动物模型中 12一个1个月的金属处理，然后进行化学致癌治疗，导致了显着的 13 PCA的增加和癌性病变的增长和癌变的动物的增加和增加的趋势 在PB处理的动物中14。重要的是，单细胞RNASEQ分析表明PB是相关的 15随着Preslc的亚群的扩展，并具有上皮谱系标记为基质 - 16像致癌细胞一样，而IAS与罕见，独特的亚群的出现有关 17个与“癌症”干细胞相似的致癌Preslc。该应用程序将检验以下假设 18 IAS和/或PB在亚群中的特异性和/或PB的特异性和/或可能不同的信号通路 19前列腺上皮样细胞（Preslc），以启动或增加癌变的风险 20腺。这是前列腺致癌领域和退伍军人的一个未经测试的假设 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使用PCA形成测定的肾移植模型在体内的上皮干细胞（Preslc）。 23我们将评估金属在免疫缺陷宿主小鼠中体内形成PCA的影响，这是 24具有PCA化学诱导的或没有化学诱导； 2）用金属特异性表征茎状细胞 25个转录组签名。我们将使用单细胞RNA测序和可视化信息 26确定特征是金属诱导的罕见亚群的独特基因特征 27 Preslcs种群中的癌症干细胞。我们的目标是应用这些基因特征来丰富 28 FACS的罕见亚群，并评估其致癌潜力。我们还将利用 29癌症基因组ATLAS PCA数据和其他在线数据库，以实现准确的分类 30主要，罕见和异质亚型的Preslcs以获得金属癌发生的见解。 31拟议工作的发现可能会解决与职业和职业后有关的问题 32部署暴露并扩大我们对干细胞生物学的了解。潜在影响 33退伍军人卫生保健：这些研究的成功完成可能会导致 34开发新的PCA预防和治疗策略。计划减少不必要的 35暴露于这些金属离子应作为预防PCA的有效策略。 36种针对干细胞特定亚群的药物可以用作治疗选择 37防止早期PCA发展和进展。当应用于退伍军人时， 38这项研究可能允许挽救人类的生命，改善退伍军人的健康，并减少 39退伍军人人口中的残疾人数。