Developing Functional Human Cell Models to Study Initiation and Progression of Prostate Cancer between AA and EA men

开发功能性人体细胞模型来研究 AA 和 EA 男性前列腺癌的发生和进展

• 批准号: 10566633
• 负责人: Xuefeng Liu
• 金额: $ 53.78万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566633
• 关键词: Abnormal Karyotype; African American; African ancestry; American; Anchorage-Independent Growth; Androgens; Behavior; Biological; Biological Assay; Biological Process; CDK4 gene; Cancer Biology; Cancer Etiology; Cancer Model; Cancer Patient; Caring; Cell Culture Techniques; Cell Line; Cell Reprogramming; Cell model; Cells; Cessation of life; Chemoresistance; Clinical; Data; Diagnosis; Disparity; Economics; Education; Environment; Epigenetic Process; Epithelial Cells; Epithelium; Ethnic Origin; European; Exhibits; Fibroblasts; Genes; Genetic; Genomics; Goals; Human; In Vitro; Incidence; Invaded; Laboratories; Malignant Neoplasms; Malignant neoplasm of prostate; Medical; Methods; Modeling; Molecular; Mus; Mutation; Nature; Neoplasm Circulating Cells; Neuroendocrine Prostate Cancer; Oncogenes; Organoids; Pathway interactions; Patients; Phase; Phenotype; Play; Population; Predisposition; Prevention strategy; Property; Prostate; Prostatic Neoplasms; Protocols documentation; Public Health; Race; Refractory; Research; Resistance; Resources; Role; SCID Mice; Technology; Testosterone; Therapeutic Intervention; Tumor-Derived; United States; Work; Xenograft procedure; advanced prostate cancer; androgen sensitive; biobank; c-myc Genes; cancer diagnosis; cancer initiation; carcinogenesis; castration resistant prostate cancer; cell transformation; ethnic difference; exome sequencing; genetic analysis; health disparity; in vivo; male; men; metaplastic cell transformation; migration; mortality; mouse model; mutant; novel; novel strategies; outcome disparities; patient population; prostate cancer cell; prostate cancer progression; prostate cancer risk; racial difference; response; screening; social; success; tool; transcriptome; transdifferentiation; treatment strategy; tumor; tumor progression

Project Summary Prostate cancer (PCa) is the most frequently diagnosed male cancer and the second leading cause of cancer deaths in men in the United States. This growing public health challenge is aggravated by disparities in the incidence and mortality of PCa between African-American (AA) and European-American (EA) men. For example, the incidence of PCa is almost 60% higher in AA men and the mortality rate 2-3 times greater. While access to medical care may contribute to these differences, other studies suggest that cell-based differences may play a critical role. Unfortunately, no primary human prostate cell cultures are available for interrogating potential cellular alterations during early carcinogenesis. Organoid culture models work well for growing normal prostate cells and advanced PCa, but fail to succeed with primary PCa. CR (Conditional Reprogramming) culture, which was developed by Dr. Liu (PI) and his colleagues, is changing the landscape for generating in vitro human cancer models. CR technology allows to establish cell cultures from normal prostate, primary PCa and advanced PCa. CR cells from normal epithelium can fully differentiate when placed in conditions that mimic their natural environment, while CR cells from a primary prostate tumor exhibit an abnormal karyotype and form tumors in SCID mice. In the current application, in an effort to define the biological basis for their clinical disparities, we first propose to probe primary AA and EA normal prostate cells for differences in their susceptibility to immortalization and transformation. Then, we will determine response of biobanked normal and tumor CR cells to testosterone from AA and EA patients in presence or absence of their corresponding fibroblasts. Then, we will compare the genetic and biological properties of tumor CR cultures from AA and EA patients, including migration/invasion, anchorage-independent growth, tumor formation in presence or absence of their corresponding fibroblasts. Finally, we will compare genetically, epigenetically and phenotypically CR cells from AA and EA patients with metastatic and castration resistant PCa. Upon completion of this application, we will have established a living biobank with novel functional cell models, including matched normal and tumor prostate CR cells and their corresponding fibroblasts from AA and EA patients, immortalized AA and EA prostate cell lines and transformed AA and EA cell lines with annotated genomic and patient’s clinical information. These novel models include prostate cells at normal, primary PCa and advanced PCa and will provide an invaluable and novel resource for studies of initiation and progression and health disparity studies of PCa.

项目摘要 前列腺癌（PCa）是最常见的男性癌症，也是第二大癌症原因 美国男性的死亡率。这一日益严重的公共卫生挑战因以下因素而加剧： 非洲裔美国人（AA）和欧洲裔美国人（EA）男性之间PCa发病率和死亡率。为 例如，AA男性中PCa的发病率几乎高60%，死亡率高2-3倍。而 获得医疗保健可能有助于这些差异，其他研究表明，基于细胞的差异， 可能会起到关键作用。不幸的是，没有原代人前列腺细胞培养可用于询问 在早期癌变过程中潜在的细胞变化。类器官培养模型对于正常生长的 前列腺细胞和晚期前列腺癌，但未能成功与原发性前列腺癌。CR（Conditional Reprogramming） 刘博士（PI）和他的同事们开发的文化正在改变世界上产生的景观。 体外人类癌症模型。CR技术允许从正常前列腺、原发性PCa 先进的PCa。正常上皮细胞的CR细胞在一定条件下可以完全分化， 模拟其自然环境，而来自原发性前列腺肿瘤的CR细胞表现出异常核型 并在SCID小鼠中形成肿瘤。在本申请中，为了定义其生物学基础， 临床差异，我们首先提出探测原代AA和EA正常前列腺细胞的差异， 对永生和转化的敏感性。然后，我们将确定生物样本库正常值的响应 和肿瘤CR细胞对来自AA和EA患者的睾酮在存在或不存在其相应的 成纤维细胞然后，我们将比较来自AA和EA的肿瘤CR培养物的遗传和生物学特性 患者，包括迁移/侵袭、锚定非依赖性生长、存在或不存在肿瘤形成 相应的成纤维细胞。最后，我们将比较遗传，表观遗传和表型CR 来自患有转移性和去势抵抗性PCa的AA和EA患者的细胞。在完成此 应用，我们将建立一个活的生物库与新的功能细胞模型，包括匹配 来自AA和EA患者的正常和肿瘤前列腺CR细胞及其相应的成纤维细胞，永生化 AA和EA前列腺细胞系以及具有注释的基因组和患者基因组的转化的AA和EA细胞系 临床信息。这些新模型包括正常、原发性PCa和晚期PCa的前列腺细胞， 将为启动和进展以及健康差异的研究提供宝贵和新颖的资源 研究PCa。