This project is dedicated to understanding more about the topic area of malignant mesothelioma (MM). Findings of the project are expected to clarify molecular mechanisms by which environmental exposure can alter biology of a cell and result in development of MM. In addition, the outcome of our project may also help in identification of predictive and prognostic biomarkers of asbestos exposure related to development of MM.

MM is a very aggressive cancer of pleural or peritoneal mesothelial cells caused by asbestos exposure. Military veterans are at increased risk of developing this cancer because of history of exposure with asbestos. In a large study Navy or shipyard exposures accounted for about one-third of all MM cases. As the latency period of development of MM is very long (10-50 years) following asbestos exposure, the cases of MM will continue to appear for decades to come. Because of difficulties in early diagnosis and resistance to conventional therapies, MM remains a challenge to clinicians. Although in recent years significant progress has been made in unraveling the mechanisms of interaction of mesothelial cells to asbestos fibers, resulting modulation of signaling pathways, and genetic and epigenetic events, the critical question remains, how inhaled asbestos fibers in lungs communicate to remotely present mesothelial cells to cause MM. In the present project, we propose to understand how asbestos-exposed macrophages and lung epithelial cells communicate to remotely present pleural and peritoneal mesothelial cells. We hypothesize that exosomes, tiny vesicles (30-100 nm) secreted from macrophages and epithelial cells in response to asbestos exposure can carry the information (chemical messenger) relevant for mesothelial cell transformation. Exosomes are known to communicate with adjacent as well as distant cells. We rationalize that although the first cells to encounter inhaled asbestos are epithelial cells and macrophages, it is the secreted exosomes from these cells that carry the information to pleural or peritoneal mesothelial cells that educate them to develop into MM. We also hypothesize that exosomes from primary MM tumors can help in local spreading and progression of the disease. These basic studies on exosomes will be extended in humans, in which the exosomes from blood plasma of normal, asbestos-exposed individuals, and MM patients will be analyzed for their protein signature. These translational studies in humans may help in identifying lead candidates of biomarkers for asbestos exposure and early MM diagnosis.

The outcome of this study will help in advancing the field of MM. In the short term, it will be a step forward in understanding the mechanism of MM development and identification of biomarkers of asbestos exposure, which may lead to early diagnosis of MM. In the long term, with further research, we may identify biomarkers of MM progression and design therapies to target them.

This research is a combination of basic and translational, eventually leading to therapy. The basic part will deal with understanding the mechanism of MM development after asbestos exposure. Identification of exosome protiens in asbestos exposed plasma from human will support in vitro basic research and at the same time may help in identifying biomarkers for asbestos exposure and early diagnosis of MM. Identification of exosome molecular markers involved in MM tumor progression will help in designing targeted therapy for MM.

Preliminary data generated from this proposal will be used for a grant application to different mechanisms to generate more clinically relevant outcome in next 5 years or so.

Outcome of this study may help in advancing the field of MM by providing early diagnosis as well as potential targets for therapy.

As MM is a devastating disease for military service members due to service-related exposure to asbestos, outcome of our project will have a huge impact on them in terms of early diagnosis and/or therapy.