Lung cancer is a multifactorial disease caused by a cascade of genetic events, including changes in cell cycle checkpoint and progression, cell proliferation, and chromosome stability, which leads to the development of a primary carcinoma. After establishment of the primary tumor, changes in normal cell adhesion and motility subsequently allow these tumor cells to escape from the original tumor, migrate to secondary sites, and grow anew. The acquisition of this capacity in the primary tumor frequently results in clinically incurable disease, and these secondary tumors, or metastases, are a significant contributor to mortality and morbidity in lung cancer patients. Several genetic lesions on chromosome 9 at position 9p21 have been associated with lung cancer. Among these is the focal adhesion protein Talin-1, which is involved in cell adhesion and motility. Talin-1 levels are decreased in certain lung cancer cells. The HYPOTHESIS to be evaluated is that dysregulation of Talin-1 leads to altered cell adhesion leading to anchorage-independent growth of cells in the primary tumor. Acquisition of this phenotype then increases the invasiveness of these cells and results in the development of metastatic lung cancer.
SPECIFIC AIMS. This hypothesis will be addressed by (1) determining the molecular basis for the Talin-1 deficiency at the gene, mRNA, and protein levels in lung cancer cells; (2) determining the role of Talin-1 in lung cancer cell adhesion, migration, and invasion, with particular emphasis on the behavior of lung cancer cells in three-dimensional culture matrices that mimic the cellular environment in vivo; and (3) extending these studies to a broad panel of lung cancer cell lines representing each histological class of lung cancer so that previously unknown general features of metastatic lung cancer will be identified. SIGNIFICANCE. These studies will provide insight into the molecular and cellular mechanisms of lung cancer progression and determine whether Talin-1 is a suppressor of metastasis in lung cancer. These studies will also lead to the development of new prognostic indicators and therapeutic strategies for treatment of metastatic lung cancer.
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