Role of Nuclear Pore-Regulated Mechanisms in Prostate Cancer Aggressiveness

核孔调节机制在前列腺癌侵袭性中的作用

基本信息

批准号：
10059202
负责人：
Veronica Rodriguez-Bravo
金额：
$ 37.95万
依托单位：
THOMAS JEFFERSON UNIVERSITY
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：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10059202
关键词：
Address Advanced Development Anaphase Androgen Receptor Automobile Driving Binding Biochemical Biochemical Genetics Biochemistry Biological Assay Biological Process Cancer Patient Carcinoma Castration Cell Death Cell Survival Cells Chemoresistance Chromatin Chromosome abnormality Clinical Clinical Management Computer Analysis Coupled Cytogenetics Data Data Set Defect Development Disease Dissection Epigenetic Process Evaluation Experimental Models Future Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Transcription Genome Genome Stability Genomic approach Goals Human Immunohistochemistry Importins In Vitro Laboratories Lead Link Malignant Neoplasms Malignant neoplasm of prostate Metastatic Prostate Cancer Microscopy Mitosis Mitotic Mitotic Activity Mitotic Checkpoint Modeling Molecular Target Nuclear Pore Nuclear Pore Complex Nuclear Pore Complex Proteins Oncogenic Organoids Outcome Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Pharmacology Phosphotransferases Play Post-Translational Protein Processing Pre-Clinical Model Production Property Prostate Prostatic Neoplasms Protein Isoforms Proteomics Publishing Receptor Signaling Refractory Refractory Disease Regulation Research Proposals Resistance Resolution Role Sampling Solid Neoplasm Testing Therapeutic Intervention Tissue Sample Transcriptional Regulation Tumor Tissue Up-Regulation Validation Variant Work advanced prostate cancer aurora B kinase clinical development clinical efficacy clinically relevant clinically significant cofactor cohort efficacy testing functional genomics genetic approach genome integrity high resolution imaging human disease improved in vivo inhibitor/antagonist inner centromere protein innovation live cell imaging microscopic imaging neoplastic cell novel novel marker novel therapeutic intervention nucleocytoplasmic transport pre-clinical predictive marker prevent prostate cancer cell prostate cancer model prostate cancer progression response therapy resistant transcription factor transcriptomics tumor tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Advanced carcinomas are among the most lethal human diseases, being metastatic prostate cancer (PC) a classic example. Despite current treatments, metastatic PC progresses to a therapy resistant stage that precedes lethality. Therefore, there is a need to identify new targetable mechanisms driving cancer aggressiveness to continue improving patients’ outcome. The main objective of this research proposal is to dissect the mechanisms by which Nuclear Pore Complexes (NPCs) regulate genome functions (gene expression and integrity) in PC and uncover novel NPC-regulated targetable pathways using innovative pre-clinical models of lethal PC. NPCs contribute to different biological functions through their building blocks nucleoporins (Nups), including nucleo-cytoplasmic transport, chromatin organization, gene expression, genome integrity and mitotic regulation. In the context of cancer, Nups have been associated to tumor formation and development, however their specific mechanistic role in cancer pathogenesis remains largely unknown. Recently we identified clinically relevant Nups upregulated in lethal PC through interrogation of publicly available patient tissue sample transcriptomic datasets containing primary and castration-chemotherapy-resistant metastatic prostate tumors. Within the upregulated Nups, POM121 was shown to play a role in the aggressiveness of lethal PC (cell survival, proliferation and tumorigenesis) via nuclear transport regulation. Yet, the specific transport-dependent and - independent mechanisms by which POM121 regulates the aggressive features of PC and its crosstalk with other Nups remain unknown. Notably, functional genomic studies (transcriptomic and computational analysis) combined with biochemical and single-cell high-resolution imaging have revealed a crosstalk between two top upregulated Nups in lethal PC, POM121 and TPR, which impacts on the aggressiveness properties of PC cells. Specifically, we found that PC cell survival is enhanced by the POM121 transcriptional regulation of specific genome stability genes and TPR, which in turn regulates mitotic checkpoint activity, through Androgen Receptor (AR)-dependent and independent mechanisms. Crucially, our studies have also uncovered a potential novel role of soluble chromatin-bound Nups in the regulation of aggressive features of PC cells potentially through direct transcriptional regulation. Thus, collectively these results led to the hypothesis that NPCs regulate PC aggressiveness through multifaceted mechanisms controlling both genome functions and stability. We will address this hypothesis and determine the Nup-specific mechanisms contributing to PC aggressiveness through three aims. In Aim 1, we will define POM121 nuclear transport-dependent and -independent mechanisms promoting PC aggressiveness. In Aim 2, we will examine the POM121-TPR mechanistic interplay enhancing genome stability and cell survival in lethal PC. In Aim 3, we will evaluate the clinical significance and efficacy of targeting specific NPC-regulated pathways controlling genome integrity in patient derived pre-clinical models.

项目概要晚期癌症是最致命的人类疾病之一，其中包括转移性前列腺癌 (PC) 典型的例子是，尽管目前正在进行治疗，转移性 PC 仍会进展到治疗抵抗阶段。因此，需要确定新的癌症驱动机制。继续改善患者预后的积极性本研究提案的主要目标是剖析核孔复合体 (NPC) 调节基因组功能（基因表达）的机制和完整性），并使用创新的临床前模型发现新的 NPC 调节的靶向途径致命的 PC 通过其构建模块核孔蛋白 (Nups) 发挥不同的生物功能，包括核质运输、染色质组织、基因表达、基因组完整性和有丝分裂然而，在癌症的背景下，Nups 与肿瘤的形成和发展有关。最近我们在临床上发现它们在癌症发病机制中的具体机制作用仍然很大程度上未知。通过询问公开的患者组织样本，致死性 PC 中的相关 Nups 上调包含原发性和去势化疗耐药的转移性前列腺肿瘤的转录组数据集。在上调的 Nups 中，POM121 在致命 PC 的攻击性（细胞存活、增殖和肿瘤发生）通过核转运调节然而，特定的转运依赖性和 - POM121 通过独立机制调节 PC 的攻击性特征及其与其他设备的串扰值得注意的是，功能基因组研究（转录组学和计算分析）仍然未知。结合生化和单细胞高分辨率成像揭示了两个顶部之间的串扰致死性 PC、POM121 和 TPR 中的 Nups 上调，这会影响 PC 细胞的侵袭性。具体来说，我们发现特定的 POM121 转录调节可增强 PC 细胞的存活率。基因组稳定基因和 TPR，反过来通过雄激素受体调节有丝分裂检查点活性至关重要的是，我们的研究还发现了一种潜在的新作用。可溶性染色质结合 Nups 可能通过直接调节 PC 细胞的侵袭性特征因此，这些结果共同得出了 NPC 调节 PC 的假设。我们将通过控制基因组功能和稳定性的多方面机制来实现攻击性。解决这一假设并通过以下方式确定导致 PC 攻击性的 Nup 特定机制：在目标 1 中，我们将定义 POM121 核运输依赖和独立机制。在目标 2 中，我们将研究 POM121-TPR 机械相互作用增强。在目标 3 中，我们将评估致命性 PC 中的基因组稳定性和细胞存活率。针对患者衍生的临床前模型中控制基因组完整性的特定 NPC 调节途径。