YB-1 - master regulator of mesothelioma malignancy

Malignant pleural mesothelioma (MPM) is an extremely aggressive cancer caused by the inhalation of asbestos fibres. Patients suffering from this disease experience one of the worst cancer-related survival rates. With currently available therapies, only 5% of patients survive longer than 5 years after diagnosis. While the correlation between asbestos exposure and MPM incidence is irrefutable, the mechanisms behind how this mineral causes cancer are still not well understood. A better understanding of the underlying pathobiology is the most likely course to the development of more successful therapies for any disease. Our project will characterise an important biological molecule, the Y-box binding protein-1 (YB-1), that we hypothesise to be a central driver of the aggressive behaviour of MPM. Our preliminary data show that YB-1 is involved in the growth, migration, invasion and resistance to chemotherapy of MPM cells. We are also the first to show that YB-1 is secreted by cells in response to contact with asbestos, and that this soluble YB-1 (sYB-1) drives increased migration of both non-cancerous mesothelial cells and malignant MPM cells. We hypothesise that YB-1 secretion and its subsequent interaction with other cells is a key step in both the initial tumour development and the subsequent progression of MPM. We also hypothesise that YB-1 is a potent driver of malignancy in MPM and therefore can serve as an intriguing new target for treatment and/or a marker for early detection of MPM and indication of the most beneficial treatment. Our project will focus on 3 aims: i) to investigate the mechanisms behind and significance of YB-1 secretion and its role in early development and progression of MPM, ii) evaluate YB-1 as a novel therapeutic target and iii) evaluate the diagnostic, prognostic and predictive significance of this protein. To achieve the first aim, we will expose normal mesothelial and tumour cells to asbestos fibres and characterize the secretion of YB-1. Also, cells will be treated with or forced to overexpress YB-1 and we will analyse malignant characteristics such as cell growth, migration, invasion and drug resistance. The second aim will be addressed by targeting YB-1 specifically using small interfering RNA in combination with chemotherapy, irradiation and targeted therapy to identify potential synergistic effects. The most promising of these (in addition to YB-1 knockdown alone) will be tested in vivo using an intraperitoneal mouse model. Finally, we will measure YB-1 levels in the serum, pleural effusions and tumour tissue of patients and compare these to healthy controls. Our project YB-1 master regulator of mesothelioma malignancy therefore has the potential to bring a new therapeutic target and clinically relevant biomarker to the sparsely populated table of tools for MPM management.