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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：
10558020
负责人：
Veronica Rodriguez-Bravo
金额：
$ 35.29万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-29 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10558020
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.

项目总结