Integrative Functional Profiling of Tumor-Derived Extracellular Vesicles

肿瘤来源的细胞外囊泡的综合功能分析

• 批准号: 10679069
• 负责人: Liang Xu
• 金额: $ 6.45万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679069
• 关键词: 3-Dimensional; Acceleration; Address; Advanced Development; Biological Markers; Biological Process; Biosensing Techniques; Biosensor; Blinded; Blood; Breast Cancer Patient; Breast Cancer cell line; Cell Communication; Cell Line; Cells; Characteristics; Classification; Clinical; Clinical Research; Clinical Treatment; Development; Devices; Diagnosis; Diagnostic; Dimensions; Disease; Disease model; Disease stratification; Drug resistance; Early Diagnosis; Engineering; Epithelium; Evolution; Extracellular Matrix; Face; Genetic Complementation Test; Goals; Human; In Vitro; MMP14 gene; Malignant Neoplasms; Matrix Metalloproteinases; Measures; Mediating; Mediator; Membrane; Mesenchymal; Metastatic/Recurrent; Methods; Microfluidic Microchips; Microfluidics; Modality; Molecular; Monitor; Mus; Nanochip Analytical Device; Neoplasm Metastasis; Patients; Performance; Phenotype; Pilot Projects; Plasma; Process; Prognosis; Property; Protein Analysis; Proteins; Recurrent disease; Relapse; Reporting; Research; Sampling; Signal Transduction; Solid Neoplasm; Specimen; Staging; System; Technology; Testing; Therapeutic; Training; Translating; Tumor Burden; Tumor Cell Invasion; Tumor Promotion; Tumor-Derived; Validation; Vesicle; accurate diagnosis; biomarker panel; cancer diagnosis; chemotherapy; clinical diagnosis; clinical implementation; cohort; disease diagnosis; drug relapse; drug testing; early detection biomarkers; exosome; experimental study; extracellular vesicles; follow-up; improved; in vivo; innovation; liquid biopsy; lithography; machine learning algorithm; malignant breast neoplasm; microfluidic technology; mouse model; nanoengineering; nanopattern; nanovesicle; new technology; next generation; novel; optimal treatments; patient derived xenograft model; patient stratification; personalized cancer therapy; personalized management; precision medicine; precision oncology; prognostic; protein expression; prototype; response; self assembly; technology validation; tool; treatment response; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression; validation studies

PROJECT SUMMARY Clinical implementation of Precision Medicine faces major challenges in precision disease stratification and staging, determining optimal treatment, monitoring therapy response, and overcoming drug resistance and relapse. To address these challenges, there is a critical unmet need for better biomarkers and tests that complement current methods for accurate diagnosis, prognosis and monitoring of response to treatments. Liquid biopsy presents an innovative non-invasive modality for precision oncology as it promises to provide a global view of tumor dynamics. Extracellular vesicles (EVs), including exosomes, are emerging as a new paradigm of liquid biopsy for non-invasive cancer diagnosis and monitoring. Exosomes are 40-150 nm membrane vesicles secreted by most cells and have been identified as essential mediators of cell interactions and signaling that promote tumor metastasis, drug resistance, and relapse. Despite the potential clinical impact of these findings, precise biological functions of exosomes, including matrix metalloproteinases (MMPs)-mediated modulation of tumor microenvironments, and their potential clinical value remain yet to be determined. This is due in part to the daunting challenges in isolation and analysis of these nanovesicles with diverse molecular and functional properties. Here we hypothesize that functional phenotypes of circulating exosomes can provide potent biomarkers for detecting early malignancy, monitoring tumor progression and metastasis, and assessing therapy response in breast cancer. To test this hypothesis, we propose the advanced development and validation of a nano-engineered microfluidic biosensing system capable of integrative analysis of both molecular and functional phenotypes of exosomes in one streamlined workflow. The research will be performed by three specific aims: 1) Expand the MINDS strategy to develop an optimal 3D nano-engineered integrative EV molecular and activity profiling (EV-MAP) nanochip platform; 2) Adapt and optimize the EV-MAP technology for monitoring tumor burden and therapy response using mouse models; and 3) Evaluate and validate the EV-MAP technology for potential applications to clinical diagnosis and classification of breast cancer patients. The new technology will confer superior analytical capabilities to substantially accelerate the functional studies of circulating exosomes. Harnessing exosome activities for diagnostic, prognostic or therapeutic benefit presents a paradigm-shifting mechanism for precision medicine. While focused on breast cancer in this project, our research will ultimately create a transformative tool for studies of a wide range of bioactive exosomes in various malignancies to develop reliable non-invasive liquid biopsy of cancer.

项目概要 精准医疗临床实施面临精准疾病分层和精准化的重大挑战 分期、确定最佳治疗、监测治疗反应以及克服耐药性和 复发。为了应对这些挑战，迫切需要更好的生物标志物和测试来满足这些需求 补充当前准确诊断、预后和治疗反应监测的方法。液体 活检为精准肿瘤学提供了一种创新的非侵入性方式，因为它有望提供全球性的 肿瘤动力学的观点。细胞外囊泡（EV），包括外泌体，正在成为一种新的范例 用于非侵入性癌症诊断和监测的液体活检。外泌体是 40-150 nm 的膜囊泡 由大多数细胞分泌，并已被确定为细胞相互作用和信号传导的重要介质 促进肿瘤转移、耐药和复发。尽管这些发现具有潜在的临床影响， 外泌体的精确生物学功能，包括基质金属蛋白酶（MMP）介导的调节 肿瘤微环境及其潜在的临床价值仍有待确定。这部分是由于 分离和分析这些具有不同分子和功能的纳米囊泡面临着艰巨的挑战 特性。在这里，我们假设循环外泌体的功能表型可以提供有效的 用于检测早期恶性肿瘤、监测肿瘤进展和转移以及评估治疗的生物标志物 乳腺癌的反应。为了检验这个假设，我们提出了一个先进的开发和验证 纳米工程微流控生物传感系统，能够对分子和功能进行综合分析 在一个简化的工作流程中检测外泌体的表型。该研究将通过三个具体目标进行：1） 扩展 MINDS 战略，开发最佳的 3D 纳米工程一体化 EV 分子和活性 分析（EV-MAP）纳米芯片平台； 2）调整和优化用于监测肿瘤的EV-MAP技术 使用小鼠模型的负担和治疗反应； 3) 评估和验证 EV-MAP 技术 在乳腺癌患者的临床诊断和分类中的潜在应用。新技术将 赋予卓越的分析能力，大大加速循环外泌体的功能研究。 利用外泌体活性实现诊断、预后或治疗益处带来了范式转变 精准医疗机制。虽然本项目的重点是乳腺癌，但我们的研究最终将 创建一种变革性工具，用于研究各种恶性肿瘤中的多种生物活性外泌体，以开发 可靠的非侵入性癌症液体活检。