Identification and Characterization of Metastasis-Related Protein Marker for Non-Small Cell Lung Cancer by Quantitative Tissue and Pleural Effusion Proteomes

Lung cancer is one of the most prominent causes of cancer death over the world. Non-small cell lung cancer (NSCLC) is the most common lung cancer type, comprising ~80% of all lung cancers. The stage of lung cancer is highly correlated to prognosis and mortality, specifically, the degree of cancer spread to lymph nodes (LNs) is the determining factor in the accurate staging and would be the basis for surgery and adjuvant treatment. However, because of the limited diagnostic approach, the diagnosis/prognosis of NSCLC patients has improved only minimally in the past decade. Thus, it is emergent to find a good biomarkers for detection of disease progress or metastasis to stratify the patients with the respect of risk for micrometastasis and disease aggressiveness. In this proposal, to gain the metastasis-related biomarkers, we first generate the differentially expressed protein profiles from two types of clinical specimens by quantitative proteomics technologies. One is the lung cancer tissues with different extent of LN involvement (N0, no regional LN involvement; N1, involvement of ipsilateral intrapulmonary, peribronchial, or hilar LNs; N2, involvement of ipsilateral mediastinal or subcarinal LNs; M, distant metastasis) and the other is the pleural effusion (PE) from NSCLC patients with malignancy or benign pulmonary diseases. The tissue proteome/phosphoproteome allows us to search the biomarkers as well as molecular mechanisms underlying lung cancer tumorigenesis. We will also integrate the differential tissue proteome/phosphoproteome, PE proteome and cancer cell secretome to generate a potential body fluid accessible biomarker dataset for lung cancer metastasis based on literature search, functional classification, network analysis and novelty. The potential metastasis-related biomarkers will be validated by using large scale of clinical specimens. To address the molecular mechanisms of these metastasis-related biomarkers, we will combine molecular biology, cell biology, quantitative proteomics and xenograft mice models to characterize the regulations of these proteins involved in lung cancer progression. This proposal would be the first study to search metastasis-related biomarker for NSCLC by integration of quantitative tissue proteome, PE proteome and secretome. The goal of this proposal is to discover clinical useful biomarker and address the mechanism of metastasis-related biomarker for prognosis and therapeutic development of NSCLC. Our specific aims are: 1. Generate metastasis-related biomarker datasets for NSCLC. a. Generate a metastasis-related tissue proteome/phosphoproteome dataset by identification and quantification of protein profiles from paired adenocarcinoma cancer tissues with different extent of LN involvement. b. Generate a malignancy-related PE proteome dataset by identification and quantification of protein profiles from six types of PEs. 2. Develop a biomarker panel for prognosis of NSCLC. a. Pathway analysis of metastasis-related tissue proteome/phosphoproteome. b. Combine tissue proteome, PE proteome and cancer cell secretome to search metastasis-related biomarker candidates those are originating from cancer cells and could be detected in body fluids. c. Select potential biomarkers based on literature search, functional classification, network analysis and novelty. d. Validate the clinical significance of metastasis-related biomarkers by using large scale of clinical specimens. 3. Determine the molecular mechanism of the promising biomarkers in lung cancer metastasis. a. Characterize the biological functions of biomarker in cell and xenograft mouse model. b. Define the relationship between promising biomarker and well-known signaling molecules or discover the novel interaction network of promising biomarker by quantitative proteomic strategy

Project ID:PC10301-0904
External Project ID:NSC101-2320-B182-035-MY3