Early and frequent screening for colorectal cancer will enable detection of localized early-stage tumors while they are still treatable, thus significantly reducing the drastic mortality rate associated with this disease. To achieve this, we propose to take the novel approach of combining lipidomic and proteomic analysis of colorectal cancer-derived exosomes in an effort to prevent colon cancer by improving our understanding of colorectal cancer biology and cell-cell communication and by defining a catalogue of tissue-specific markers that can be used as tools to screen, stage, and follow the treatment of patients. Exosomes are unique encapsulated vesicles that are secreted from cells and transported away from the originating site to interact with their localized environment or transported around the body through blood. Their unique proteomic profiles are specific to the tumor cell and thus provide an opportunity to define tissue origin and status. This information can be used to improve diagnostic strategies for the prevention of late stage colorectal cancer and to gain further insight into colorectal cancer biology. First, we will define a purification protocol for normal colon epithelial and colorectal cancer-derived exosomes. We will use newly developed lipidomic approaches to quantitatively determine the lipid profile that defines tumor-specific exosomes. The combination of lipidomic analysis and proteomic analysis, with an overlay of tissue-specific proteins will provide a set of markers that will uniquely identify tissue-specific tumor-derived exosomes that are present in many body fluids. This unique approach of integrating quantitative exosomal lipid profiles with protein profiles will ultimately advance our understanding of exosome function in colorectal cancer biology and enable the identification of highly informative and clinically useful biomarkers.

Public Health Relevance

The synergistic systems biology approach of combining lipidomics, proteomics and genomics to study disease will pave the path to improving the understanding of cancer mechanisms, diagnostic capabilities and prognostic accuracy, and will pioneer the development of new approaches that will eventually be key to individually tailored diagnostics and treatments. We aim to implement state-of-the-art lipidomics, proteomics and genomics to analyze the expressed organelle populations that we believe are fundamental indicators of cancer as a disease process. Detailed and integrated analyses of highly purified tumor-specific exosomes with lipidomic, proteomic, genomic and computational technologies will provide insights into the basic mechanism of cancer and will provide diagnostic biomarkers for early disease detection, assessment of disease progression, assessment of therapy and early detection of reoccurrences. Ultimately this will lead to enormously improved patient care, which is the principal and ultimate objective of all cancer research.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Special Emphasis Panel (ZCA1-SRLB-F (J1))
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Wagner, Paul D
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Institute for Systems Biology
United States
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