Lung cancer is the leading cause of cancer death among US Veterans, and metastatic disease is overwhelmingly the predominant cause of death. Based on our preliminary findings, we hypothesize that exosomes derived from highly motile premalignant cells can transfer metastatic phenotypes to neighboring normal cells via paracrine signaling. In the current Veteran Affairs (VA) Merit Review funding period, we identified and selected a subpopulation of highly migratory premalignant airway epithelial cells that were observed to migrate through microscale constrictions at up to 100-fold the rate of the control unselected cells. These highly migratory cells demonstrate enhanced metastatic behavior in vivo. We isolated and characterized exosomes from these highly migratory premalignant human airway epithelial cells, as well as, malignant pleural effusion (MPE)-derived metastatic cancer cells. In both settings of premalignancy and metastatic disease, exosomes containing unique omic signatures transferred the metastatic phenotype to non-motile cells. From these signatures, we have identified potential candidates mediating the transfer of metastatic behavior and immunosuppression. To facilitate the study of metastatic disease, we will utilize our MPE-biobank for exosome isolation and characterization from individual patient's MPE-derived metastatic lung cancer cells. While exosomes are known to serve as functional mediators in cell interaction leading to cancer metastasis, this will be the first comprehensive study to fully characterize the mechanisms underlying these events in the context of pulmonary premalignant migration, as well as, in the context of metastatic cells from MPEs. In order to characterize and understand the mechanisms of this process in regulating the promotion of migratory capacity and immunosuppression in premalignant and metastatic lung cancer cells we will: 1) Determine the capacity of exosomes to drive disease progression across the spectrum of disease in NSCLC by characterizing the exosomal cargo derived from premalignant and metastatic cancer cells, 2) Determine the mechanisms of exosome-dependent promotion of epithelial mesenchymal transition (EMT) and migratory capacity of epithelial and lung cancer cells and, 3) determine the mechanisms of exosome-dependent immune suppression. While exosomes have been reported to serve as functional mediators in cellular interaction leading to cancer metastasis, this will be the first comprehensive study to fully characterize the mechanisms underlying the full spectrum of disease, both in the context of pulmonary premalignant migration as well as metastatic lung cancer. This study of exosome mediated metastatic-modulation in the context of premalignancy and metastasis is unique and will help define the biology of occult metastasis, provide insights into the phenomenon of parallel progression, increase the possibility of biomarker discovery and provide targets for lung cancer interception.
Lung cancer is the leading cause of death among U.S. Veterans. Each year lung cancer exacts a devastating toll in terms of lives lost and resources expended. Recent studies suggest that early metastatic disease may be caused by cells that have an enhanced capacity for rapid movement. This research will identify the mechanisms of rapid cellular movement that underlies early metastatic disease. This will allow the development of new agents that can prevent metastatic activity, thus profoundly shifting the approach to the treatment of lung cancer.