Characterization and targeting the CXCR2-STAT-1/3 axis in metastatic Ewing sarcoma

转移性尤文肉瘤中 CXCR2-STAT-1/3 轴的表征和靶向

• 批准号: 10208507
• 负责人: Atreyi Dasgupta
• 金额: $ 41.25万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-02 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208507
• 关键词: Address; Adolescent and Young Adult; Automobile Driving; Biological; Biological Assay; Bone neoplasms; Cell Culture Techniques; Cell Line; Cell Proliferation; Cells; ChIP-seq; Chemotherapy-Oncologic Procedure; Childhood; Clinical Data; Clinical Trials; Coculture Techniques; Communication; Complement; Critical Pathways; DNA Binding; Data; Development; Diagnosis; Disease; Environment; Ewings sarcoma; Fibroblasts; Funding Mechanisms; Genes; Genetic; Goals; Growth; Human; IL8RB gene; In Vitro; Interleukin-8B Receptor; Investigation; Knowledge; Lead; Ligands; Localized Disease; Lung; Malignant Bone Neoplasm; Mediating; Mediator of activation protein; Metastatic Ewing' s Sarcoma; Metastatic to; MicroRNAs; Mission; Modality; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patients; Pediatric Neoplasm; Pharmacology; Phenotype; Physiological; Pre-Clinical Model; Primary Neoplasm; Prognosis; Proteins; Proteomics; Radiation therapy; Regulation; Research; Resources; Role; STAT1 gene; Sampling; Signal Transduction; Specimen; Stromal Cells; Survival Rate; Technology; Therapeutic; Translating; Translations; Transplantation; Tumor Biology; United States National Institutes of Health; Up-Regulation; Vesicle; Xenograft Model; Xenograft procedure; cytokine; differential expression; extracellular vesicles; in vivo; in vivo Model; innovation; insight; lung metastatic; migration; multiple omics; nano-string; novel; novel therapeutic intervention; pre-clinical; preclinical study; sarcoma; small molecular inhibitor; therapeutic target; transcriptome sequencing; transcriptomics; tumor; tumorigenic

Project Summary Ewing Sarcoma (EwS) is the second most common bone tumor in children. At diagnosis, approximately 25-30% of patients with EwS have metastatic disease. For localized disease, systemic chemotherapy regimen along with surgery and/or radiotherapy has significantly increased the survival rate of patients to approximately 70%. Unfortunately, the prognosis for metastatic EwS has remained dismal, with a 5-year survival rate of 20–30%. This prognosis has not changed in last several decades. Thus, it is imperative to focus on the mechanisms of EwS metastasis and identify specific biological features of the metastatic tumor. In this regard, it is important to study the tumor biology not in isolation, but in the context of the tumor stroma, to better understand the interaction between the sarcoma cells and the tumor associated stromal cells that facilitates EwS metastatic growth. Given the limitation in representative vertebrate models for EwS, our approach of integrating tumor intrinsic and stromal factors that lead to metastatic phenotypes is closer to the physiological context than studying the tumor in isolation. Using serial transplantation approaches, we have generated novel lung metastatic EwS cell lines. Cytokine analysis from co-culture of these cells with lung fibroblast cells, revealed upregulation of several cytokines, including CXCL-1/2, CXCL-5, and CXCL-8, which are ligands to the receptor CXCR2. This observation was confirmed from transcriptomic analysis using Nanostring technology from paired primary with lung metastatic patient samples. Further, integrated analysis of proteomics from multiple metastatic models, converged on STAT1 as a significantly differentially expressed protein in metastatic samples. Thus, through the integration of multi-omic approaches on relevant innovative in vivo metastatic models and human patient specimens, we have identified a novel molecular mechanism of metastasis in EwS that we can readily assess using our unique resources. Our overarching hypothesis is that the CXCR2-STAT1 axis is a critical pathway in metastatic EwS and an attractive therapeutic target. To address this hypothesis, and to bridge the current gaps in knowledge and potential therapeutic opportunities, we propose two innovative, translation and exploratory aims. Aim1 will characterize the tumorigenic effects of the CXCR2-STAT1 pathway in primary and metastatic tumor by identifying STAT1 regulated genes induced by CXCR2 and assessing genetic and pharmacological inhibition of this pathway as a novel therapeutic intervention. Aim2 will investigate the role of extra cellular vesicles, as an intercellular mediator of tumor-stroma communication that facilitates CXCR2-STAT1 signaling by micro RNA (miRNA) regulation. The treatment of aggressive and metastatic Ewing sarcomas remains a challenge therapeutically. Successful completion of our aims will provide novel molecular, and valuable pre- clinical therapeutic insights for metastatic Ewing sarcoma.

项目摘要 尤文肉瘤（EwS）是儿童第二常见的骨肿瘤。诊断时，约25-30% 的EwS患者患有转移性疾病。对于局限性疾病，全身化疗方案沿着 手术和/或放射治疗显著地将患者的存活率提高到大约70%。 不幸的是，转移性EwS的预后仍然很差，5年生存率为20- 30%。 这种预测在过去几十年里没有改变。因此，必须着重研究 EwS转移，并确定转移性肿瘤的特定生物学特征。在这方面， 不是孤立地研究肿瘤生物学，而是在肿瘤间质的背景下研究肿瘤生物学，以更好地了解相互作用 在肉瘤细胞和肿瘤相关基质细胞之间，促进EwS转移生长。给定 EwS代表性脊椎动物模型的局限性，我们整合肿瘤内在和间质的方法 导致转移表型的因素更接近生理背景，而不是研究肿瘤在 隔离使用系列移植方法，我们已经产生了新的肺转移性EwS细胞系。 这些细胞与肺成纤维细胞共培养的细胞因子分析显示， 细胞因子，包括CXCL-1/2、CXCL-5和CXCL-8，它们是受体CXCR 2的配体。这 使用Nanostring技术，从配对的原发性和非原发性肿瘤的转录组学分析中证实了观察结果。 肺转移患者样本。此外，来自多种转移模型的蛋白质组学的综合分析， 在转移性样本中，STAT 1作为显著差异表达的蛋白质聚集。因此通过 多组学方法在相关创新体内转移模型和人类患者上整合 标本，我们已经确定了一种新的分子机制转移EwS，我们可以很容易地评估 利用我们独特的资源。我们的总体假设是CXCR 2-STAT 1轴是一个关键途径， 转移性EwS和有吸引力的治疗靶点。为了解决这一假设，并弥合目前的差距， 在知识和潜在的治疗机会，我们提出了两个创新，翻译和探索 目标。Aim 1将描述CXCR 2-STAT 1通路在原发性和转移性肿瘤中的致瘤作用。 通过鉴定CXCR 2诱导的STAT 1调节基因并评估遗传和药理学 抑制该途径作为一种新的治疗干预。Aim 2将研究细胞外的作用， 囊泡，作为肿瘤间质通讯的细胞间介质，通过以下方式促进CXCR 2-STAT 1信号传导： microRNA（miRNA）调控。侵袭性和转移性尤文肉瘤的治疗仍然是一个 治疗挑战我们的目标的成功完成将提供新的分子，和有价值的前， 转移性尤文肉瘤的临床治疗见解。