Integrators of Metastatic Potential

转移潜能积分器

基本信息

批准号：
10357854
负责人：
Pradipta Ghosh
金额：
$ 49.87万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357854
关键词：
Actins Address Advanced Malignant Neoplasm Animal Model Antineoplastic Agents Biological Assay Biological Markers Biological Models Biology Biosensor Blood Breast Cancer Cell Cancer Biology Cause of Death Cells Cellular biology Clinical Data Detection Development Disease Disease Progression Drug Targeting Engineering Environment Fluorescence Resonance Energy Transfer Foundations Frequencies Genes Goals Heterogeneity Image Immune system In Situ Lesion Local Therapy Lung Neoplasms Malignant Neoplasms Mammary Neoplasms Measures Metastatic breast cancer Methods Microscopy Molecular Mus Names Neoplasm Metastasis Normal Cell Oncogenic Patient Care Patients Peptides Pharmaceutical Preparations Phosphoproteins Phosphorylation Positioning Attribute Precision Medicine Initiative Primary Neoplasm Process Prognostic Marker Proteins Proteome Quality of life Reporter Research Risk Seeds Signal Pathway Signal Transduction Signaling Molecule Solid Neoplasm Sorting - Cell Movement Stream Technology Testing Tumor Escape Uncertainty Vascular System Vesicle Xenograft procedure Zebrafish anticancer research base cancer cell cancer heterogeneity cancer stem cell cancer therapy cell motility cell type cellular imaging chemotherapy clinical implementation design drug development drug discovery effectiveness evaluation established cell line experimental study fluorescence imaging fluorescence lifetime imaging high risk improved in vivo in vivo imaging malignant breast neoplasm metastatic process molecular imaging molecular subtypes molecular targeted therapies mouse model multi-photon neoplastic cell novel overtreatment patient derived xenograft model patient stratification patient subsets personalized screening precision medicine premalignant prevent quantitative imaging receptor screening side effect success synergism tool tumor tumorigenic

项目摘要

ABSTRACT One key goal of the NCI Precision Medicine Initiative focuses on development of new tools to tailor cancer therapy to disease status and risk of metastasis-- Patients at high risk for metastatic disease would receive aggressive, frequently molecularly-targeted therapy, whereas those with low risk for metastatic disease would be treated with appropriate local therapies, sparing them toxic side effects of therapy while maintaining high likelihood for cure. One of the main challenges preventing implementation of precision medicine for metastasis is limited understanding of signaling molecules and pathways that confer high metastatic potential to a small subset of cancer cells within a larger, heterogeneous tumor. Consequently, molecular imaging of metastatic ‘potential’ is an unvanquished challenge. To engineer biosensors that can detect and measure metastatic 'potential' of single living cancer cells, we carried out a comprehensive analysis of the pan-cancer phosphoproteome to search for actin-remodelers required for cell migration, that are enriched in cancers, but excluded in normal cells. Only one phosphoprotein emerged, tyr-phosphorylated CCDC88A (GIV/Girdin), a bona-fide metastasis-related protein across a variety of solid tumors. We designed multi-modular biosensors that are partly derived from GIV, and because GIV integrates pro-metastatic signaling by multiple oncogenic receptors, we named them ‘Integrator-of-Metastatic- Potential (IMP)'. It is hypothesized that single cell imaging of GIV activation using IMPs, rather than simply levels of GIV expression, will detect the subset of metastasis-initiating cells that must be eliminated to prevent metastatic disease. Preliminary experiments demonstrate that IMPs captured the heterogeneity of metastatic potential within primary lung and breast tumors at steady-state, detected those few cells which have acquired the highest metastatic potential and tracked their enrichment during metastasis. These findings provide proof- of-concept that IMPs can measure the diversity and plasticity of metastatic potential of tumor cells in a sensitive and unbiased way. Going forward, IMPs will be optimized and validated for use as tools for molecular imaging of metastasis-initiating cells via 3 goals: 1) Image metastatic potential of single breast cancer cells; 2) Image GIV activation as a marker of Metastasis Initiating Cells (MICs); and 3) Image metastatic potential in patient- derived xenografts. To accomplish these goals, this multi PD/PI proposal capitalizes on synergy of non- overlapping expertise of two PIs and two animal model systems (zebrafish and mice), in-depth biology of a novel signaling pathway, and cutting-edge technology of in vivo imaging. Success in detecting metastasis-initiating cells will be a transformative advance for cancer cell biology. It will pave the path for the development of personalized screening platforms to assess the effectiveness of anti- cancer drugs in killing the highly tumorigenic cells within any given tumor, and ultimately enable clinical implementation of precision cancer therapy to improve treatment and quality of life for patients.

抽象的 NCI Precision Medicine Iniative的一个主要目标是开发新工具来调整癌症治疗疾病状况和转移风险 - 转移性疾病高风险的患者将接受侵略性，经常靶向分子的疗法，而转移性疾病风险较低的疗法将接受适当的局部疗法治疗治愈的可能性。阻止实施转移精确医学的主要挑战之一对信号分子和途径的理解有限，该途径会导致高转移电位与小型转移电位在较大的异质肿瘤内癌细胞的子集。因此，转移性的分子成像 “潜力”是一个毫无争议的挑战。对于可以检测和测量单个活癌细胞转移性“潜力”的工程生物传感器，我们对Pan-Cantcer磷蛋白组进行了全面分析，以搜索肌动蛋白转换器细胞迁移所必需的，这些细胞迁移富含癌症，但在正常细胞中排除。只有一种磷蛋白出现，py磷酸化的CCDC88A（GIV/GIRDIN），这是一种善意的转移相关蛋白实体瘤。我们设计了部分源自GIV的多模块化生物传感器，并且因为GIV 多个致癌接收器的综合促进信号传导，我们将其命名潜力（IMP）'。假设使用IMPS的GIV激活的单细胞成像，而不是简单 GIV表达的水平将检测到必须消除的转移启动细胞的子集，以防止转移性疾病。初步实验表明，Imps捕获了转移的异质性在稳态下原发性肺和乳腺肿瘤内的潜力，检测到了少数获得的细胞转移性最高的潜力，并在转移过程中追踪了它们的富集。这些发现提供了证明 - 概念的IMP可以测量敏感的肿瘤细胞转移性潜力的多样性和可塑性和公正的方式。展望未来，IMPS将经过优化和验证，以用作分子成像的工具通过3个目标进行转移性启动细胞的形象：1）单个乳腺癌细胞的图像转移性潜力； 2）图像 GIV激活是转移启动细胞（MIC）的标志； 3）患者的图像转移潜力 - 派生的Xenographictics。为了实现这些目标，该多PD/PI提案资本利用了非 - 两个PI和两个动物模型系统（斑马鱼和小鼠）的重叠专业知识，一种新颖的生物学信号通路和体内成像的尖端技术。在检测转移促进细胞方面的成功将是癌细胞生物学的变革性进步。它将为开发个性化筛查平台的发展铺平道路，以评估反 - 癌症药物在任何给定肿瘤内杀死高度肿瘤细胞，并最终使临床实施精确癌症治疗以改善患者的治疗和生活质量。