Centrosome instability as a mechanism to promote localized prostate cancer

中心体不稳定是促进局部前列腺癌的机制

基本信息

批准号：
9815223
负责人：
ANNE E CRESS
金额：
$ 55.8万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-22 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9815223
关键词：
3-Dimensional Address Aneuploidy Automobile Driving Basal Cell Biochemical Biogenesis Carcinoma in Situ Cells Centrosome Characteristics Chemicals Chromosomal Instability Chromosomes Clustered Regularly Interspaced Short Palindromic Repeats Copy Number Polymorphism Coupled Cultured Cells Cytoplasmic Organelle DNA Methylation DNA Sequence Alteration Data Disease Down-Regulation Early Diagnosis Early treatment Epithelial Cells Event Evolution Genomic Instability Goals Human Hypoxia In Situ Indolent Knowledge Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mediating Microtubules Mission Mitotic Mitotic spindle Molecular Morphology Mus Mutation Nuclear Atypia Oncogenic Organ Organelles Organoids PLK1 gene Patients Physiological Prostate Prostate Adenocarcinoma Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Public Health Recurrence Reporting Research Role Series Structure System Testing Therapeutic Tissue Microarray Tumor Suppressor Genes United States National Institutes of Health Work Xenograft Model attenuation base cancer diagnosis cancer therapy carcinogenesis chromothripsis genome integrity human tissue improved innovation insight methylation pattern molecular marker mouse model neoplastic cell novel precision oncology predictive marker prostate carcinogenesis treatment strategy tumor tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT There is a fundamental gap in our knowledge to explain the origin of prostate cancer (PCa). Unlike many cancers, PCa lacks signature mutations in key oncogenes and tumor-suppressor genes and, instead, displays large-scale genomic instability. We propose to study subcellular organelle instability as a mechanism that results in genomic instability in epithelial cells of the prostate gland. Specifically, we focus on centrosomes, tiny cytoplasmic organelles that dramatically influence genome integrity. Centrosomes can become subcellular pathognomonic structures when they are amplified, as is the case in many different cancers, causing mitotic errors, genomic instability and inducing tumorigenesis in mouse models. Likewise, centrosome loss causes mitotic errors and genomic instability identical to centrosome amplification, but has not been reported in cancer. We discovered recently that human prostate adenocarcinoma lack centrosomes, providing a novel mechanistic explanation for genomic instability in PCa. Our long-term goal is to discover the abnormal changes that underlie prostate tumorigenesis, malignancy and recurrence, and to improve PCa diagnosis and treatment strategies. The objective of this application is to determine the contribution of centrosome loss in driving genomic instability resulting in PCa and to determine the molecular mechanistic basis for centrosome disappearance. Drawn from our preliminary data, our central hypothesis is that hypoxia is a key physiologically-relevant determinant of centrosome loss in the prostate which, in turn, stimulates genomic instability and tumorigenesis. The rationale for the proposed research is to address the provocative question of how cancer-specific changes in subcellular pathognomonic structures (specifically, centrosome loss) transpire and contribute to carcinogenesis. This hypothesis will be tested in three specific aims: 1) Determine whether centrosome loss is triggered by hypoxia in prostate cells and tumors; 2) Determine whether centrosome loss drives genomic instability in normal prostate epithelial cells and promotes tumorigenesis; and 3) Determine if centrosome loss is characteristic of high-grade prostatic intraepithelial neoplasia (PIN, carcinoma in situ). The approach is innovative because it investigates a novel mechanism of subcellular organelle instability during prostate tumorigenesis: specifically, that hypoxia and centrosome biogenesis are mechanistically coupled as drivers of genomic instability in prostate tumor formation. The proposed research is significant because it tests a new concept that the loss of a critical subcellular organelle is responsible for PCa genomic instability, which is both a hallmark and agent of prostate tumor evolution. If we are correct, centrosome loss will be a tangible event early in the genesis of human prostate cancer, providing new early detection and treatment strategies.

项目概要/摘要我们在解释前列腺癌 (PCa) 起源方面的知识存在根本性差距。与许多人不同与癌症相比，PCa 缺乏关键癌基因和肿瘤抑制基因的特征突变，相反，显示出大规模的基因组不稳定性。我们建议研究亚细胞器的不稳定性作为导致前列腺上皮细胞基因组不稳定的机制。具体来说，我们重点中心体，微小的细胞质细胞器，极大地影响基因组完整性。中心体可以当它们被放大时，它们会变成亚细胞特有的结构，就像许多不同的情况一样癌症，导致有丝分裂错误、基因组不稳定并诱导小鼠模型中的肿瘤发生。同样，中心体丢失会导致有丝分裂错误和与中心体相同的基因组不稳定性扩增，但尚未在癌症中报道。我们最近发现人类前列腺腺癌缺乏中心体，为腺癌基因组不稳定性提供了新的机制解释前列腺癌。我们的长期目标是发现前列腺肿瘤发生的异常变化，恶性肿瘤和复发，并改进 PCa 诊断和治疗策略。此举的目的应用程序是确定中心体丢失在驱动基因组不稳定中的贡献，从而导致 PCa 并确定中心体消失的分子机制基础。取自我们的初步数据，我们的中心假设是缺氧是一个关键的生理相关决定因素前列腺中心体丢失，进而刺激基因组不稳定和肿瘤发生。这拟议研究的基本原理是解决癌症特异性变化如何产生的挑衅性问题。亚细胞特异结构（特别是中心体丢失）蒸腾并有助于致癌作用。该假设将在三个具体目标上进行检验：1）确定中心体是否丢失由前列腺细胞和肿瘤缺氧引发； 2）确定中心体丢失是否驱动正常前列腺上皮细胞的基因组不稳定性并促进肿瘤发生； 3) 确定是否中心体丢失是高级前列腺上皮内瘤变（PIN，原位癌）的特征。该方法具有创新性，因为它研究了亚细胞器不稳定的新机制在前列腺肿瘤发生过程中：具体来说，缺氧和中心体生物发生在机制上是耦合作为前列腺肿瘤形成中基因组不稳定性的驱动因素。拟议的研究意义重大因为它测试了一个新概念，即关键亚细胞细胞器的丢失导致前列腺癌基因组不稳定性，这既是前列腺肿瘤进化的标志，也是其推动因素。如果我们是对的，中心体丢失将是人类前列腺癌发生早期的一个有形事件，提供了新的早期发现和治疗策略。