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：
10300992
负责人：
Veronica Rodriguez-Bravo
金额：
$ 3.04万
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 2022-01-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10300992
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 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.

项目摘要晚期癌是最致命的人类疾病之一，是转移性前列腺癌（PC）A 经典示例。尽管目前治疗，但转移性PC仍发展为抗治疗阶段先于致命性。因此，有必要确定驱动癌症的新的目标机制侵略性继续改善患者的结果。该研究建议的主要目的是剖析核孔复合物（NPC）调节基因组功能的机制（基因表达 PC中的完整性），并使用创新的临床前模型发现了新型NPC调节的可定位途径致命PC。 NPC通过其构建块核电蛋白（NUPS）促进不同的生物学功能，包括核胞质转运，染色质组织，基因表达，基因组完整性和有丝分裂规定。在癌症的背景下，NUP与肿瘤形成和发育有关，但是它们在癌症发病机理中的特定机械作用在很大程度上仍然未知。最近我们在临床上确定了通过询问公开可用的患者组织样本，在致命PC中更新了相关的NUPS 含有原发性和castatration-化学疗法的转移性前列腺肿瘤的转录组数据集。在更新的NUP中，POM121被证明在致命PC的侵略性中起作用（细胞存活，通过核转运调节的增殖和肿瘤发生）。但是，特定的运输依赖性和 - POM121的独立机制调节PC的侵略性及其与其他的串扰 NUP仍然未知。值得注意的是，功能基因组研究（转录组和计算分析）结合生化和单细胞的高分辨率成像，揭示了两个顶部之间的串扰在致命PC，POM121和TPR中上调NUP，这会影响PC细胞的侵略性。具体而言，我们发现POM121的转录调节提高了PC细胞的存活率基因组稳定基因和TPR，进而调节有丝分裂检查点活性，通过雄激素受体（AR）依赖性和独立机制。十足的是，我们的研究也发现了潜在的新作用在调节PC细胞的侵略性特征的调节中可能通过直接的转录调节。这些结果总的来说导致了NPC调节PC的假设通过控制基因组功能和稳定性的多方面机制的侵略性。我们将解决这一假设，并确定通过三个目标。在AIM 1中，我们将定义POM121核转运依赖性和非依赖性机制促进PC侵略性。在AIM 2中，我们将检查POM121-TPR机械相互作用增强致命PC中的基因组稳定性和细胞存活。在AIM 3中，我们将评估临床意义和效率针对特定的NPC调节的途径，该途径控制患者衍生的临床前模型中的基因组完整性。