Cancer Cell Mechanical Profiling Analysis

癌细胞机械分析

• 批准号: 9571227
• 负责人: JIANYU RAO
• 金额: $ 20.36万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9571227
• 关键词: Address; Atomic Force Microscopy; Biological Markers; Bladder; Bladder irrigation procedure; Body Fluids; California; Cancer Diagnostics; Cancer Model; Carcinoma; Carcinoma in Situ; Cells; Clinical; Clinical Research; Collaborations; Complex; Comprehensive Cancer Center; Cystectomy; Cytology; Cytometry; Cytopathology; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Disseminated Malignant Neoplasm; Early Diagnosis; Elasticity; Epigenetic Process; Event; Foundations; Future; Genetic; Goals; In Vitro; Individual; Institutes; Label; Lead; Lesion; Liquid substance; Malignant - descriptor; Malignant Neoplasms; Measurement; Measures; Mechanics; Medical center; Methods; Microfluidics; Modeling; Molecular Analysis; Monitor; Morphology; Nanotechnology; Nature; Neoplasm Metastasis; Normal Cell; Patients; Pattern; Performance; Permeability; Phase; Pleural; Premalignant Cell; Process; Prognostic Marker; Property; Qi; Randomized; Research Personnel; Sampling; Scanning Probe Microscopes; Science; Screening for cancer; Signal Pathway; Structure; Study models; Technology; Testing; Therapeutic; Transitional Cell Carcinoma; Translating; Tumor Cell Invasion; Urine; cancer biomarkers; cancer cell; cancer diagnosis; cancer therapy; cancer type; carcinogenicity; cell behavior; clinical application; clinical diagnostics; diagnostic biomarker; drug sensitivity; improved; mechanical properties; microfluidic technology; molecular marker; multidisciplinary; nano; nanocytology; nanosystems; new technology; novel; novel marker; performance tests; prognostic; programs; prospective; success; tumor progression

ABSTRACT Built on the success of collaboration of our multi-disciplinary team of investigators from UCLA Medical center, Jonsson Comprehensive Cancer Center (JCCC), and California Nanosystem Institute (CNSI), we have developed a potentially new cancer diagnostic platform, called “Mechano-" or "Nanocytology”. The basic hypothesis is that as the fundamental lethal features of cancer are tumor cell invasion and metastasis, directly measuring the mechanical properties of cells associated with tumor invasion and metastasis may provide an accurate diagnostic and prognostic marker for cancer. Cancer cell mechanical signature including cell stiffness, elasticity, deformability and permeability, among others, can be quantitatively measured in label free manner at the single cell level (S. Cross, Nature Nano, 2007; Gossett, PNAS, 2012; Tsai, Science Trans. Med., 2013; Rowat, J Biol Chem 2013; Qi, Sci Rep 2015), using state of the art technologies such as Atomic Force Microscope (AFM), Deformability Cytometry (DC), and Parallel Microfiltration (PMF). These methods collectively enable robust measurements which can be implemented in a clinical setting. While data from us and others demonstrated metastatic cancer cells show rather distinctive mechanical features to morphologically similar but normal cells, there have been limited studies about how the mechanical changes occur during the multi-step carcinogenic process, or specifically focusing on a cancer type to explore the possibility of using these markers to address specific clinical questions. These important questions are essential for the long-term success of the nanocytology program. In this R21 application, we will study the changes in the mechanotypic profile of cells at various stages of cancer development and progression using a unique in vitro multi-step bladder carcinogenic model (Aim 1), and test the performance of the mechanotypic marker specifically in cytological diagnosis of urothelial carcinoma in bladder irrigation cytological fluid samples (Aim 2). For Aim 2, we will also determine if the mechnotypic markers can be used to distinguishing pre-invasive carcinoma in situ (CIS) from invasive urothelial carcinoma, a question that has substantial clinical implication in determining whether patient should receive cystectomy of not. The study will provide essential preliminary data for our eventual goal of developing the mechanotypic signature as a novel adjunct biomarker for cancer early detection. It also may lead to the development of an entirely new technology platform for quantitative, robust, and accurate determination of cancer cell behavior at the single cell level.

摘要 建立在我们来自加州大学洛杉矶分校医学中心的多学科研究团队合作成功的基础上， Jonsson综合癌症中心(JCCC)和加州纳米系统研究所(CNSI)，我们有 开发了一种潜在的新癌症诊断平台，名为“机械学”或“纳米细胞学”。最基本的 假说认为，由于癌症的基本致死特征是肿瘤细胞的侵袭和转移，直接 测量与肿瘤侵袭和转移相关的细胞的机械特性可能会提供一个 准确的癌症诊断和预后标记物。癌细胞机械特征包括细胞硬度， 弹性、可变形性和渗透性等可以在以下位置以无标签方式定量测量 单细胞水平(S.Cross，《自然纳米》，2007；Gossett，PNAS，2012；Tsai，Science Trans.医学，2013年； Rowat，J Biol Chem 2013；齐，Sci Rep 2015)，使用最先进的技术，如原子力 显微镜(AFM)、可变形性细胞术(DC)和平行微滤(PMF)。这些方法统称为 实现可在临床环境中实施的健壮测量。 虽然来自我们和其他人的数据表明，转移性癌细胞显示出相当独特的机械特征 对于形态相似但正常的细胞，关于机械变化的研究一直很有限 发生在多步骤致癌过程中，或专门针对一种癌症类型来探索 使用这些标记物解决特定临床问题的可能性。这些重要的问题是至关重要的 为了纳米细胞学项目的长期成功。在此R21应用程序中，我们将研究 用独特的体外培养技术研究癌症发展和进展不同阶段的细胞的机械分型 建立多步骤膀胱癌模型(目标1)，并对机械型标记物的性能进行特异性测试 在尿路上皮癌细胞学诊断中的应用(目的2)。对于目标2， 我们还将确定机械分型标志物是否可以用于区分浸润性癌前期原位癌 浸润性尿路上皮癌的顺应性，这一问题在确定 患者是否应该接受膀胱切除术。 这项研究将为我们开发机械签名的最终目标提供必要的初步数据 作为一种新的癌症早期检测的辅助生物标志物。它还可能导致一种全新的 用于定量、稳健和准确地确定单细胞癌细胞行为的技术平台 水平。

项目成果

Single Cell Mechanotype and Associated Molecular Changes in Urothelial Cell Transformation and Progression.

• DOI: 10.3389/fcell.2020.601376
• 发表时间: 2020
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Yu W;Lu QY;Sharma S;Ly C;Di Carlo D;Rowat AC;LeClaire M;Kim D;Chow C;Gimzewski JK;Rao J
• 通讯作者: Rao J