Molecular determinants of lung cancer progression : functional implications of the Polymeric Immunoglobulin Receptor and the Focal Adhesion Kinase
(2012)
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- (en) The central hypothesis supporting the work described here is that lung cancer development and progression is the consequence of the acquisition of multiple genetic alterations including mutations and copy number aberrations, and of the loss of tight regulatory mechanisms maintaining cellular physiological processes such as proliferation, apoptosis, and migration. The discovery of these oncogenic alterations and lost key regulatory proteins or pathways should lead to a better understanding of the disease process, and to novel diagnostic and therapeutic interventions. To test this central hypothesis, we took a dual approach: one gene-centric and the other unbiased high-throughput molecular approach. First, we hypothesized that the loss of the polymeric immunoglobulin receptor (pIgR) expression is an early event in lung cancer development and that the biology of this receptor may be implicated in tumorigenesis. This work stems from observations made in Professor Sibille’s Laboratory looking at the role of pIgR in airway biology, particularly host defense mechanisms in chronic obstructive pulmonary disease where pIgR was found to be downregulated, such as in lung cancer. We made the observation that not only pIgR expression was lost early in lung cancer development but also that restoring its function in cancer cells inhibited cellular proliferation. The mechanisms of this observation are indirect and seem to implicate loss of cellular differentiation, loss of cellular polarization, and epithelial mesenchymal transition. Next, we turned to an unbiased genome-wide approach (as opposed to a gene-centric/candidate-based approach to investigate the role of pIgR) to explore SCLC pathogenesis in an unbiased way by interrogating the cancer genome. We focused on SCLC because of the lack of progress in this devastating disease. We analyzed SCLC primary tumors by array comparative genomic hybridization based on the hypothesis that DNA copy number aberrations would allow the identification of molecular pathways of SCLC progression. This work led to the identification of the focal adhesion pathway derangement in SCLC and to a series of functional and translational studies to establish a role of the focal adhesion kinase (FAK) activation in SCLC adhesion and migration, and to correlate its expression with clinical outcomes. Finally, we undertook a high-throughput proteomic analysis to discover new molecular diagnostic and therapeutic biomarkers of SCLC. The goal was to identify membrane-specific protein biomarkers at the surface of SCLC that could be later developed into molecular imaging strategies or targeted therapies. We therefore analyzed membrane-associated protein extracts from immortalized normal bronchial epithelial, NSCLC, and SCLC cell lines by difference gel electrophoresis. This work is still ongoing but has already led to the discovery of new candidate diagnostic or therapeutic biomarkers. Various high-throughput technologies being used in this work, we also reviewed the scientific literature related to these technologies in lung cancer.
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Ocak, S. (2012). Molecular determinants of lung cancer progression : functional implications of the Polymeric Immunoglobulin Receptor and the Focal Adhesion Kinase. https://hdl.handle.net/2078.5/208052