FUS1 is a novel tumor suppressor located in the critical 3p21.3 chromosomal region frequently deleted in multiple cancers. We recently showed that Fus1-deficient mice that we generated display a complex immuno- inflammatory phenotype with a predisposition to cancer. This proposal aims to investigate the effects of the loss of tumor suppressor Fus1 on asbestos--triggered tumor initiation and growth. Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to chronic inflammation of pleural cells caused by asbestos exposure. MPM is locally invasive and notoriously chemo-resistant tumor with the survival rate of 10-12 months from the time of diagnosis. It takes about 25-50 years for a patient to develop clinical manifestations of the disease after initial asbestos exposure. Asbestos fibers lodged in the cells of the mesothelial layer cause persistent inflammation and produce genotoxic effect on mesothelial cells. In our preliminary study, we demonstrated FUS1 insufficiency in MM through different approaches. First, FUS1 down-regulation in the majority of MM specimens (~84%) was established at the mRNA and protein levels. Second, our analysis of genomic re-arrangements by Representational Oligonucleotide Microarray Analysis (ROMA) revealed a 3p21.3 loss in ~36% of MMs including stage 1 tumors. Third, pursuing a possible link between FUS1 and exposure to asbestos, we established involvement of asbestos-generated reactive oxygen species (ROS) in FUS1 down-regulation. Finally, global profiling of FUS1 transcriptional effects in MM showed that FUS1 stimulated expression of multiple genes with tumor suppressor properties and down- regulated pro-tumorigenic genes supporting its role as a tumor suppressor. In agreement with our knockout model, FUS1 up-regulated IL-15 and also modulated expression of more than 40 other genes (~20% of total FUS1-affected genes) associated with immune system. Finally, clinical significance of FUS1 transcriptional effects was validated on the expression array data produced on 30 MM and 7 control specimens. This analysis showed that ~23% of cancer-associated FUS1 targets may contribute to MPM progression and serve in future as novel therapeutic targets. Altogether these data suggest that Fus1 plays an important anti-inflammatory and anti-tumorigenic role in MPM and underscore its importance as a transcriptional regulator of immune and anti- tumorigenic pathways. We, therefore, hypothesize that the loss of FUS1 activity alters the asbestos- induced inflammatory response in the site of asbestos lodging and contributes to the development of asbestos-induced MM. This hypothesis will be tested with three specific aims:
Aim 1, will characterize the inflammatory response to asbestos in the peritoneum of Fus1-deficient mice, Aim 2, will assess susceptibility of Fus1-deficient mice to the development of asbestos-induced tumors, and Aim 3, will characterize Fus1- dependent molecular changes in the asbestos-exposed inflamed mesothelium and explore the transcriptional effect of Fus1 on the promoter of one of its target, the STRA13/bHLHB2 transcription factor.
We propose to use the Fus1 knockout mouse model that we have recently generated and characterized to delineate the role of the tumor suppression protein Fus1 in the organism's response to asbestos. We will explore susceptibility of these mice to asbestos-induced inflammation and mesothelioma and characterize Fus1-dependent molecular changes in asbestos-exposed tissues. We will also investigate into the molecular mechanisms of the Fus1 tumor suppressor and immune modulator activities, which will help in understanding the molecular basis of these processes and will provide new approaches for designing therapeutic tools for treatment of inflammation-caused diseases.
