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Identification and validation of metastasis-related molecular signatures -In-Depth and targeted proteomic analysis of epithelial-mesenchymal transition in adenocarcinomas


The spread of metastasis to distant sites is the leading cause of death from cancer. Consequently, much effort in cancer research focuses on the detection, prevention, and treatment of distant metastases. The epithelial-mesenchymal transition (EMT) phenomenon, which occurs during normal embryonic development and tissue injuries, is also activated during the progression and metastasis from numerous cancers, being responsible to turn the focal lesions into aggressive and invasive. The EMT process implicates complex changes in cancer cells and their local microenvironment which may lead to a decreased cell-cell adhesion that result to a loss of the epithelial phenotype and acquisition of mesenchymal properties conferring to cancer cells an enhanced motility and invasive ability. Factors that promote EMT in cancer are starting to be elucidated, and include tumor growth factor beta (TGF-beta), epithelial growth factor (EGF), insulin-like growth factor (IGF) among others. These factors activate several pathways including EGF, hedgehog, Wnt/b-catenin, Notch and TGF-beta. To extend and identify in more detail the molecular events at protein and post-translational levels occurring during EMT, we propose in the first stage of this project a comparative and comprehensive proteomic analysis of cell lines that represent highly incident adenocarcinomas, such as lung, breast, pancreas, ovarian and prostate, induced to EMT. The protein component of the cell surface, secretion and whole cell lysate will be extensively and quantitatively characterized by combining stable isotope amino acid labeling in cell culture (SILAC) approach with intact-protein fractionation and LC-MS/MS. With this in-depth analysis, novel potential biomarkers and molecular signatures related to the EMT process will be identified. The identified molecular signatures will be used as a basis for development of multiple reaction monitoring (MRM) methods for multiplex quantification of proteins relevant to EMT by LC-MS/MS. This platform will be applied for the high-throughput analysis of cell lines models upon multiple combinations of stimulation and more importantly to study the EMT molecular signature in tumor and plasma samples from patients with distinct types and stages of adenocarcinomas. This combined strategy, initially comprehensive and detailed, focused on the identification of candidate biomarkers and molecular signatures, followed by a targeted analysis aiming extensive validation of such candidates, will certainly uncover truly novel protein targets for extensive clinical validation focused on theranostic applications in metastatic cancer. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PALMA, CAMILA DE SOUZA; GRASSI, MARIANA LOPES; THOME, CAROLINA HASSIBE; FERREIRA, GERMANO AGUIAR; ALBUQUERQUE, DANIELE; PINTO, MARIANA TOMAZINI; FERREIRA MELO, FERNANDA URSOLI; KASHIMA, SIMONE; COVAS, DIMAS TADEU; PITTERI, SHARON J.; et al. Proteomic Analysis of Epithelial to Mesenchymal Transition (EMT) Reveals Cross-talk between SNAIL and HDAC1 Proteins in Breast Cancer Cells. MOLECULAR & CELLULAR PROTEOMICS, v. 15, n. 3, SI, p. 906-917, . (11/09740-1, 13/08135-2)

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