A transdisciplinary approach for dissecting stem cell states in prostate cancer

剖析前列腺癌干细胞状态的跨学科方法

基本信息

批准号：
10491218
负责人：
Raul Rabadan
金额：
$ 65.89万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10491218
关键词：
3-Dimensional Address Affect Androgens Automobile Driving Behavior Biological Assay Biology Cancer Biology Castration Cell Fraction Cells Colony-Forming Units Assay Complex Data Data Analyses Data Set Development Drug Targeting Epithelial Epithelial Cells Evolution Genes Genetically Engineered Mouse Heterogeneity Human Individual Investigation Knock-out Laboratories Lead Location Malignant Neoplasms Malignant neoplasm of prostate Masks Methods Modeling Molecular Molecular Profiling Mus Nature Organoids Patients Physics Process Property Prostate Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Psychological Techniques Recurrent disease Regulator Genes Research Personnel Resistance Resolution Role Sampling Specimen Statistical Models Structure Target Populations Techniques Testing Time Tissue Microarray Tissues Tumor Stem Cells Validation Work algebraic topology base cancer stem cell candidate identification candidate marker castration resistant prostate cancer cell type denoising deprivation drug candidate epigenomics experimental study innovation insight mathematical methods mouse model neuroendocrine differentiation new therapeutic target novel novel therapeutics overexpression progenitor prostate cancer cell prostate cancer model prostate cancer progression representation theory response self-renewal single cell technology single-cell RNA sequencing spatial integration stem cell biology stem cell model stem cells stem-like cell success targeted treatment theories therapeutic target therapeutically effective tool transcriptomics tumor tumor progression tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT Understanding the molecular mechanisms that drive prostate cancer progression has profound significance for defining the biology of lethal prostate cancer. The cancer stem cell model proposes that cells within a tumor are organized in a hierarchical lineage relationship and display different tumorigenic potential. This model has important translational implications since it suggests that effective therapeutics should target cancer stem cells that sustain tumor malignancy. However, despite intensive investigation, long-standing questions about the existence and properties of prostate cancer stem cells remain unresolved. To identify, characterize, and therapeutically target this population, we will combine the expertise of cancer stem cell researchers with computational/mathematical approaches. Leveraging techniques from theoretical physics (Random Matrix Theory) and algebraic topology (Topological Data Analysis), we will provide a statistical framework to dissect a molecular signature (termed CasPro) implicated in progenitor activity in prostate tumors. We will experimentally validate our findings by investigating CasPro-high cells in genetically-engineered mouse models of prostate cancer and analyzing their functional properties in assays of stem cell activities. These findings will then be further validated in studies of human prostate tumor samples, particularly from patients with treatment-resistant castration-resistant prostate cancer (CRPC). In the longer-term, we anticipate that our studies of key regulators of the stem cell signature as well as the epigenomic landscape of CasPro-high cells will identify novel targets for therapy, and lead to novel candidate drugs for these targets. Further development of candidate drugs might result in inhibition of cancer stem cell activity, thereby providing potential treatments for CRPC.

项目摘要/摘要了解驱动前列腺癌进展的分子机制对定义致命前列腺癌的生物学。癌症干细胞模型提出肿瘤内的细胞是在分层的谱系关系中组织，并显示出不同的致瘤潜力。该模型具有重要的翻译意义，因为它表明有效的治疗剂应针对癌症干细胞维持肿瘤恶性肿瘤。但是，尽管进行了深入调查，但长期存在的问题前列腺癌干细胞的存在和特性仍未解决。识别，表征和从治疗中瞄准这个人群，我们将结合癌症干细胞研究人员的专业知识计算/数学方法。利用理论物理学的技术（随机矩阵理论）和代数拓扑（拓扑数据分析），我们将提供一个统计框架来剖析分子特征（称为CASPRO）与前列腺肿瘤中的祖细胞活性有关。我们将通过实验通过研究前列腺遗传工程小鼠模型中的CASPRO高细胞来验证我们的发现癌症并分析其在干细胞活性测定中的功能特性。这些发现将是在人类前列腺肿瘤样品的研究中进一步验证，特别是耐药患者 cast割的前列腺癌（CRPC）。从长远来看，我们预计我们对关键监管机构的研究干细胞特征以及Caspro-High细胞的表观基因组景观将确定新的目标治疗，并为这些靶标提供新的候选药物。候选药物的进一步开发可能导致抑制癌症干细胞活性，从而为CRPC提供潜在的治疗方法。