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Integrators of Metastatic Potential

转移潜能积分器

基本信息

批准号：
10112849
负责人：
Pradipta Ghosh
金额：
$ 50.86万
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/10112849
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.

摘要 NCI精准医学计划的一个关键目标是开发新的工具来定制癌症根据疾病状态和转移风险进行治疗--转移性疾病高风险患者将接受积极的，经常分子靶向治疗，而那些转移性疾病的风险低，用适当的局部疗法进行治疗，使他们免受治疗的毒副作用，同时保持高的治愈的可能性。阻止转移精准医学实施的主要挑战之一对赋予小肿瘤高转移潜能的信号分子和途径的理解有限。在较大的异质性肿瘤中的癌细胞亚群。因此，转移瘤的分子成像 “潜力”是一个不可战胜的挑战。为了设计能够检测和测量单个活癌细胞转移“潜力”的生物传感器，我们对泛癌磷酸化蛋白质组进行了全面分析，以寻找肌动蛋白重塑因子细胞迁移所需的，在癌症中富集，但在正常细胞中排除。只有一种磷蛋白出现了酪氨酸磷酸化的CCDC 88 A（GIV/Girdin），这是一种真正的转移相关蛋白，存在于多种肿瘤中。实体瘤我们设计了多模块生物传感器，部分来自GIV，因为GIV 通过多种致癌受体整合促转移信号，我们将其命名为“转移整合因子”，电位（IMP）假设使用IMP的GIV活化的单细胞成像，而不是简单地 GIV表达水平，将检测必须消除以防止转移的转移起始细胞的亚群。转移性疾病初步实验表明，IMP捕获了转移性肿瘤的异质性。潜在的原发性肺和乳腺肿瘤在稳态，检测到这些少数细胞，已获得最高的转移潜力，并跟踪其在转移过程中的富集。这些发现提供了证据- IMP可以测量肿瘤细胞转移潜能的多样性和可塑性，无偏见的方式。展望未来，IMP将被优化和验证，以用作分子成像的工具通过3个目标进行转移起始细胞的成像：1）单个乳腺癌细胞的转移潜力成像; 2）单个乳腺癌细胞的转移潜力成像。 GIV活化作为转移起始细胞（MIC）的标志物;和3）成像患者中的转移潜能- 异种移植物。为了实现这些目标，该多PD/PI提案利用了非两个PI和两个动物模型系统（斑马鱼和小鼠）的重叠专业知识，信号通路和体内成像的尖端技术。成功检测转移起始细胞将是癌细胞生物学的一个变革性进展。它将为开发个性化筛选平台铺平道路，以评估抗癌症药物杀死任何给定肿瘤内的高度致瘤性细胞，并最终使临床实施精准癌症治疗，改善患者的治疗和生活质量。