Discovering proteins that explain single-cell heterogeneity in fibrillar migration

发现解释纤维迁移中单细胞异质性的蛋白质

• 批准号: 9979390
• 负责人: ANAND R ASTHAGIRI
• 金额: $ 18.35万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979390
• 关键词: 3-Dimensional; Activities of Daily Living; Automobile Driving; Blood Vessels; Breast Cancer Cell; Breast Cancer cell line; Breast Epithelial Cells; Cations; Cell Adhesion; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collagen; Collection; Complex; Data Set; Development; Disease; Exhibits; Extracellular Matrix Proteins; Future; Heterogeneity; Human; Image; Impotence; Individual; Invaded; Least-Squares Analysis; Link; Liquid Chromatography; Lymphatic; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Metastatic breast cancer; Methods; Molecular; Molecular Target; Multivariate Analysis; Neoplasm Metastasis; Organelles; Pathway interactions; Patients; Population; Population Analysis; Primary Neoplasm; Property; Proteins; Proteome; Proteomics; RNA Interference; Regulation; Resistance; Resolution; Role; Secondary to; Set protein; Shapes; Silicon Dioxide; Site; Speed; System; Testing; Therapeutic; Time; Work; analytical method; base; cancer cell; cancer subtypes; cell behavior; cell motility; in vitro Model; in vivo; individual patient; innovation; insight; laser capture microdissection; malignant breast neoplasm; migration; new technology; next generation; novel; tandem mass spectrometry; targeted treatment; therapeutic target; tumor; tumor microenvironment

Project Summary The daunting heterogeneity of breast cancer is apparent even within a tumor in an individual patient. The clinical consequence is that a targeted therapeutic e ective against some cancer cells remains impotent against counterparts that have evolved alternative pathways to accomplish disease-driving functions. Thus, there is an urgent need for single-cell approaches to discover molecular targets that span the complementary pathways by which heterogeneous cancer cells metastasize. An early step in metastasis involves cancer cells invading through the primary tumor microenvironment to reach nearby vascular and lymphatic networks through which they disseminate to secondary sites. A common mode of breast cancer invasion in the primary tumor microenvironment involves cancer cell migration along collagen bers. The proteins that regulate brillar migration are poorly understood, and the diversity of pathways by which breast cancer subtypes accomplish this invasive mode of migration remains to be elucidated. In the proposed work, we seek to develop, optimize and apply single-cell migration and proteomics (scMAP), an innovative method to quantify both the migration properties and the proteome of the same individual cell. Thus, scMAP enables the collection of a novel data set that directly links cell migration and the abundance of thousands of proteins at the single-cell level. We will apply scMAP to discover proteins whose abundance is associated with enhanced brillar migration of a panel of heterogenous breast cancer cell lines. Analysis of this novel data set by total least squares regression and mutual information will reveal proteins that exhibit quantitative linear and non-linear relationships to brillar migration properties. These results will identify distinct sets of proteins that explain the disparate brillar migration properties of heterogeneous breast cancer cells. The identi ed proteins feed a pipeline for future functional testing in complex 3d brillar matrices and subsequent potential therapeutic application to curb brillar invasive migration. In addition, scMAP opens the door to proteomic-scale, single-cell resolution insights into cell migration in other contexts, including other modes of motility in metastasis.

项目摘要 即使在单个患者的肿瘤中，乳腺癌的令人生畏的异质性也是显而易见的。的 临床结果是针对某些癌细胞的靶向治疗效果仍然无效 与已经进化出替代途径来实现疾病驱动功能的对应物进行比较。 因此，迫切需要单细胞方法来发现跨越靶区的分子靶标。 异质性癌细胞转移的互补途径。转移的早期步骤 涉及癌细胞侵入原发性肿瘤微环境到达附近的血管， 淋巴网络，它们通过这些网络传播到次级部位。乳腺癌的常见模式 在原发肿瘤微环境中的侵袭涉及癌细胞沿沿着胶原纤维迁移。的 调节brillar迁移的蛋白质知之甚少， 乳腺癌亚型实现这种侵入性迁移模式仍有待阐明。在 建议的工作，我们寻求开发，优化和应用单细胞迁移和蛋白质组学（scMAP）， 一种创新的方法来量化迁移特性和同一个人的蛋白质组 cell.因此，scMAP使得能够收集直接将小区迁移和小区迁移相关联的新数据集。 在单细胞水平上有成千上万的蛋白质。我们将应用scMAP来发现蛋白质 其丰度与一组异质性乳腺癌的增强的brillar迁移有关 细胞系用总体最小二乘回归和互信息分析这个新的数据集 将揭示与brillar迁移呈现定量线性和非线性关系的蛋白质 特性.这些结果将确定不同的蛋白质组，解释不同的brillar迁移 异质性乳腺癌细胞的特性。已识别的艾德蛋白质为未来的功能提供了管道 在复杂的3D Brillar基质中的测试以及随后抑制Brillar的潜在治疗应用 侵入性迁移此外，scMAP为蛋白质组学规模的单细胞分辨率洞察打开了大门 在其他情况下的细胞迁移，包括转移中的其他运动模式。