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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要前列腺癌 (PCa) 是最常诊断的男性癌症，也是第二大癌症原因美国男性死亡人数的差异加剧了这一日益严峻的公共卫生挑战。非洲裔美国人 (AA) 和欧洲裔美国人 (EA) 男性 PCa 的发病率和死亡率。例如，AA 男性的 PCa 发病率几乎高出 60%，死亡率则高出 2-3 倍。获得医疗保健可能会导致这些差异，其他研究表明基于细胞的差异不幸的是，没有原代人类前列腺细胞培养物可用于研究。早期致癌过程中潜在的细胞改变对于正常生长非常有效。前列腺细胞和晚期前列腺癌，但未能成功进行原发性前列腺癌 CR（条件重编程）。由刘博士（PI）和他的同事开发的文化正在改变发电的格局 CR 技术允许从正常前列腺、原发性 PCa 建立细胞培养物。来自正常上皮的晚期 PCa 细胞在处于以下条件时可以完全分化：模仿其自然环境，而来自原发性前列腺肿瘤的 CR 细胞表现出异常的核型并在 SCID 小鼠中形成肿瘤，以期确定其生物学基础。临床差异，我们首先建议探测原代 AA 和 EA 正常前列腺细胞的差异然后，我们将确定生物库正常的反应。和肿瘤 CR 细胞对来自 AA 和 EA 患者的睾酮（无论是否存在相应的睾酮）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、不依赖锚定的生长、存在或不存在肿瘤形成最后，我们将从遗传学、表观遗传学和表型方面对 CR 进行比较。完成此研究后，来自患有转移性和去势抵抗性 PCa 的 AA 和 EA 患者的细胞。应用程序，我们将建立一个具有新颖功能细胞模型的活体生物库，包括匹配的来自 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 前列腺细胞系以及带有注释基因组和患者基因组的转化 AA 和 EA 细胞系这些新模型包括正常、原发性前列腺癌和晚期前列腺癌的前列腺细胞。将为研究起始和进展以及健康差异提供宝贵的新颖资源 PCa 的研究。