Molecular Mechanisms of Large Oncosome-Induced Prostate Cancer Progression and Metastasis

大肿瘤诱导前列腺癌进展和转移的分子机制

基本信息

批准号：
10473694
负责人：
Dolores Di Vizio
金额：
$ 44.68万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473694
关键词：
Animal Model Animals Bar Codes Biological Assay Biological Process Blood Blood Circulation Bone Marrow COL1A2 gene Caliber Cancer Cell Growth Cancer Patient Castration Cell model Cells Chick Clinical Collaborations Cre-LoxP Data Disease Disease Progression Endothelium Fibroblasts Foundations Gene Deletion Genes Genetic Transcription Gleason Grade for Prostate Cancer Goals Growth Heterogeneity Human Image In Vitro Indolent Intervention Knock-out Laboratories Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mediating Mediator of activation protein Membrane Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Metastatic to Methods Modeling Molecular Morphogenesis Neoplasm Metastasis Nonmetastatic Oncogenic Oncology Pathway interactions Patient-Focused Outcomes Patients Phenotype Plasma Play Population Positioning Attribute Process Prostate Reporter Resistance Role SPI1 gene Signal Transduction Site Solid Specimen System Testing Tissues Tumor-Derived Vesicle Work androgen sensitive angiogenesis base cancer cell cancer type castration resistant prostate cancer cell stroma clinically significant conditioning exosome experimental study extracellular vesicles genome editing host neoplasm interaction in vivo innovation intercellular communication machine learning method men molecular oncology nano-string novel programs prostate cancer cell prostate cancer metastasis prostate cancer model prostate cancer progression response trafficking tumor tumor growth tumor microenvironment tumor progression uptake

项目摘要

Abstract Prostate cancer (PC) is one of the most frequent tumors in men. Despite recent progress, the disease is still incurable once resistance to castration therapy occurs. Tumor progression is strongly mediated by altered molecular exchanges between cancer cells and the surrounding milieu that originate at the primary sites. However, the mechanisms regulating the response of the stroma to the tumor, which ultimately promote PC progression are still largely unknown. Our laboratory discovered a new type of tumor-derived extracellular vesicle (EV), which are referred to as “large oncosomes” (LO), can harbor more abundant molecular cargo that is distinct and more potently bioactive than that carried by exosomes. The rationale for this proposal derives from our preliminary observations in patients that LO abundance in the circulation correlates with PC progression. Our functional data demonstrate that LO can activate oncogenic signaling in fibroblasts, which respond to LO uptake by activating MYC and SPI1 and by induce a transcriptional program that promotes angiogenesis and stimulates tumor growth. The overarching goal of this project is to determine the functional role of LO in PC progression and metastasis. We hypothesize that LO functionally reprogram normal prostate-associated fibroblasts (NAF) toward a phenotype that is driven by MYC and SPI1 activation. These results strongly suggest that tumor-derived LO might activate intercellular responses that are specific to this subtype of extracellular vesicle. Our hypothesis will be tested with three Specific Aims: Aim 1: To investigate the role of LO-induced fibroblast activation in PC progression. Aim 2: To find evidence that the LO- induced transcriptional program is active in PC patients with clinically significant disease. Aim 3: To test if LO and/or Exo derived from PC patient and PDX specimens promote castration resistance and/or bone metastasis. We will use a combination of complementary in vitro and animal orthotopic models as well as focused approaches involving genome editing, molecular barcodes, and a Cre-Lox reporter in vivo system. Our study will determine if the transcriptional program induced by LO in vitro drives tumor progression and metastasis in vivo. Additionally we will determine if this transcriptional program can also be identified in patient specimens and if it indicative of tumor progression. Finally, our study will provide evidence for LO abilities to induce metastasis of indolent PC cells.

抽象的前列腺癌（PC）是男性最常见的肿瘤之一，尽管最近取得了进展，但该疾病仍然无法治愈。一旦发生对去势治疗的抵抗，肿瘤进展就会受到分子的强烈介导。然而，癌细胞与起源于原发部位的周围环境之间的交换。调节基质对肿瘤的反应，最终促进 PC 进展的机制是我们的实验室发现了一种新型的肿瘤来源的细胞外囊泡（EV），其在很大程度上仍然未知。被称为“大肿瘤体”（LO），可以容纳更丰富的独特且更有效的分子货物该提议的基本原理源自我们的初步观察。我们的功能数据表明，循环中 LO 丰度与 PC 进展相关的患者。 LO 可以激活成纤维细胞中的致癌信号，成纤维细胞通过激活 MYC 和 SPI1 来响应 LO 摄取，并通过诱导促进血管生成和刺激肿瘤生长的转录程序。该项目旨在确定 LO 在 PC 进展和转移中的功能作用。将正常前列腺相关成纤维细胞 (NAF) 功能性重编程为由 MYC 驱动的表型这些结果强烈表明，肿瘤源性 LO 可能会激活细胞间反应。针对这种细胞外囊泡亚型，我们的假设将通过三个具体目标进行检验：目标 1：研究 LO 诱导的成纤维细胞激活在 PC 进展中的作用目标 2：寻找 LO- 的证据。诱导转录程序在患有临床显着疾病的 PC 患者中活跃。目标 3：测试 LO 是否存在。和/或源自PC患者和PDX标本的Exo促进去势抵抗和/或骨转移。我们将结合使用互补的体外和动物原位模型以及重点我们的研究将涉及基因组编辑、分子条形码和体内 Cre-Lox 报告系统等方法。确定 LO 体外诱导的转录程序是否驱动体内肿瘤进展和转移。此外，我们将确定该转录程序是否也可以在患者标本中识别，以及是否可以最后，我们的研究将为 LO 诱导肿瘤转移的能力提供证据。惰性 PC 细胞。