Nano-Engineered Lab-on-a-Chip for Assessing HuR-Regulated Exosomes for Cancer Monitoring and Targeted Therapy

纳米工程芯片实验室用于评估 HuR 调节的外泌体以进行癌症监测和靶向治疗

• 批准号: 10627821
• 负责人: DAN ALAN DIXON
• 金额: $ 58.17万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627821
• 关键词: 3-Dimensional; 3D Print; Address; Adopted; Animal Model; Binding; Biological; Biological Assay; Biological Markers; Biology; Biosensing Techniques; Blood; Breast Cancer Cell; Cancer Biology; Cancer Patient; Cancer cell line; Cell Communication; Cell Line; Cell Proliferation; Cell secretion; Cells; Chemicals; Chemistry; Circulation; Clinical; Clinical Research; Collaborations; Colon Carcinoma; Colorectal Cancer; Companions; Cytolysis; Data; Detection; Devices; Diagnosis; Disease; Drug resistance; Early Diagnosis; Engineering; Face; Fingerprint; Gastroenterology; Goals; Growth; HuR protein; Human; In Vitro; Invaded; Lab On A Chip; Laboratories; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Measures; Mediator; Membrane; Messenger RNA; Methods; Modality; Modification; Molecular; Molecular Profiling; Monitor; Mus; Nanochip Analytical Device; Nanostructures; Neoplasm Metastasis; Oncogenic; Outcome; Pathologic; Patient Recruitments; Patient-Focused Outcomes; Pattern; Plasma; Precision therapeutics; Printing; Prognosis; Prognostic Marker; Protein Analysis; Proteins; RNA; RNA-Binding Proteins; Recurrence; Reproducibility; Resistance; Resolution; Role; Sampling; Standardization; Surface; System; Technology; Testing; Tissue Sample; Translational Research; Tumor Burden; Tumor Markers; Tumor stage; Tumor-Derived; Validation; Vesicle; angiogenesis; cancer cell; cancer diagnosis; cancer therapy; clinical implementation; clinically relevant; colon cancer patients; detection platform; diagnostic biomarker; engineered exosomes; exosome; fabrication; human model; improved; in vivo; in vivo Model; inhibitor; invention; liquid biopsy; malignant breast neoplasm; microdevice; mouse model; nanodevice; nanoengineering; nanomaterials; nanoscale; nanovesicle; neoplastic cell; new technology; next generation; non-invasive monitor; noninvasive diagnosis; novel; novel diagnostics; overexpression; patient derived xenograft model; personalized management; personalized medicine; precision medicine; precision oncology; protein biomarkers; prototype; research clinical testing; response; screening; self assembly; small molecule; targeted cancer therapy; targeted treatment; technology platform; tool; tumor; tumor diagnosis; tumor initiation; tumor progression; tumorigenesis

PROJECT SUMMARY Novel diagnostic and prognostic biomarkers are urgently needed to improve clinical outcomes of cancer. Circulating exosomes are emerging as a new paradigm of “liquid biopsy” for non-invasive cancer diagnosis and monitoring. Exosomes are small membrane vesicles of 30-150 nm in size that are secreted by most cells, and growing evidence has shown important biological roles and clinical relevance of exosomes. In various cancers, tumor-derived exosomes have been found to be accumulated in human biofluids, such as blood, and enriched with a set of biomolecules from the cells of origin, such as specific proteins and RNAs, which may constitute a “tumor signature”. However, the evaluation of clinical value of exosomes has been limited in part due to challenges in isolation and analysis of such small, dynamic and molecularly diverse vesicles. To address this obvious gap in both analytical technologies and precision medicine, here we propose to an Exosome Fingerprinting Nano-Device (ExoFIND) system that offers unprecedented analytical capabilities for measuring intravesicular protein markers carried by tumor-derived exosomes present in circulation. This new technology will be adapted to examining exosomes derived from cell lines, animal models and human biofluids to assess exosomal proteins, including Hu antigen R (HuR), as potential liquid biopsy-based markers for early diagnosis, prognosis, and targeted therapy of cancer. The proposed studies will be carried out to accomplish four Specific Aims: 1) Develop a general, high-resolution inkjet colloidal printing technology for standardized and scalable fabrication of 3D nanoengineered bioassay devices; 2) Establish a 3D nano-engineered ExoFIND system for integrative analysis of exosomal fingerprints of tumors; 3) Adapt and validate the ExoFIND system as a blood-based detection platform to assess colorectal cancer (CRC)-derived exosomes as biomarkers for tumor initiation and progression; 4) Adapt and validate the ExoFIND system as a companion assay to monitor tumor response, drug resistance and prognosis of HuR-targeted therapy. Successfully carried out, our study will provide important impetus to: (1) develop next-generation technologies with transformative and reproducible analytical capabilities and minimal sample requirement, and (2) catalyze the exploration of exosomes as a novel paradigm of liquid biopsy for precision oncology. Our overarching goal is to ultimately provide a transformative platform technology for basic and translation investigation of a wide range of malignancies and diseases.

项目概要 迫切需要新的诊断和预后生物标志物来改善癌症的临床结果。 循环外泌体正在成为非侵入性癌症诊断和治疗的“液体活检”的新范例。 外泌体是大多数细胞分泌的大小为 30-150 nm 的小膜囊泡，并且 越来越多的证据表明外泌体在各种领域具有重要的生物学作用和临床相关性。 癌症、肿瘤来源的外泌体被发现在人类生物体液中积累，例如血液和 富含一组来自起源细胞的生物分子，例如特定的蛋白质和 RNA，这可能 然而，外泌体的临床价值评估受到部分限制。 由于分离和分析如此小的、动态的和分子多样化的囊泡面临挑战。 为了解决分析技术和精准医学方面的这一明显差距，我们在此提出 外泌体指纹识别纳米设备 (ExoFIND) 系统提供前所未有的分析能力 测量循环中存在的肿瘤来源的外泌体携带的囊泡内蛋白质标记物。 该技术将适用于检查源自细胞系、动物模型和人类生物体液的外泌体 评估外泌体蛋白，包括 Hu 抗原 R (HuR)，作为潜在的基于液体活检的早期标记物 将进行所提出的研究来完成癌症的诊断、预后和靶向治疗。 四个具体目标： 1）开发通用、高分辨率喷墨胶体打印技术，用于标准化 3D 纳米工程生物测定装置的可扩展制造；2) 建立 3D 纳米工程 ExoFIND； 肿瘤外泌体指纹综合分析系统；3）调整和验证ExoFIND系统； 作为基于血液的检测平台，用于评估结直肠癌 (CRC) 衍生的外泌体作为生物标志物 肿瘤发生和进展；4) 调整和验证 ExoFIND 系统作为监测的伴随检测 HuR靶向治疗的肿瘤反应、耐药性和预后我们的研究成功进行。 将为以下方面提供重要推动力：（1）开发具有变革性和可扩展性的下一代技术 可重复的分析能力和最少的样品需求，以及（2）促进探索 外泌体作为精准肿瘤学液体活检的新范例，我们的首要目标是最终实现这一目标。 为广泛的基础和翻译研究提供变革性平台技术 恶性肿瘤和疾病。

项目成果

Microfluidic circulating reactor system for sensitive and automated duplex-specific nuclease-mediated microRNA detection.

• DOI: 10.1016/j.talanta.2021.122396
• 发表时间: 2021-09-01
• 期刊: TALANTA
• 影响因子: 6.1
• 作者: Zhou, Xin;Cao, Hongmei;Zeng, Yong
• 通讯作者: Zeng, Yong

Molecular and functional extracellular vesicle analysis using nanopatterned microchips monitors tumor progression and metastasis.

• DOI: 10.1126/scitranslmed.aaz2878
• 发表时间: 2020-06-10
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Zhang P;Wu X;Gardashova G;Yang Y;Zhang Y;Xu L;Zeng Y
• 通讯作者: Zeng Y

The RNA-binding protein HuR in human cancer: A friend or foe?

• DOI: 10.1016/j.addr.2022.114179
• 发表时间: 2022-05
• 期刊: Advanced drug delivery reviews
• 影响因子: 16.1

Stress granules in colorectal cancer: Current knowledge and potential therapeutic applications.

结直肠癌中的应激颗粒：当前知识和潜在的治疗应用。

• DOI: 10.3748/wjg.v26.i35.5223
• 发表时间: 2020-09-21
• 期刊: World journal of gastroenterology
• 影响因子: 4.3
• 作者: Legrand N;Dixon DA;Sobolewski C
• 通讯作者: Sobolewski C

Niclosamide improves cancer immunotherapy by modulating RNA-binding protein HuR-mediated PD-L1 signaling.

• DOI: 10.1186/s13578-023-01137-w
• 发表时间: 2023-10-17
• 期刊: CELL AND BIOSCIENCE
• 影响因子: 7.5
• 作者: Zhang, Qi;Yang, Zhe;Hao, Xinbao;Dandreo, Lauren J.;He, Lily;Zhang, Yuxia;Wang, Fen;Wu, Xiaoqing;Xu, Liang
• 通讯作者: Xu, Liang