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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.

摘要