Additional supervisor: Prof Janne Lehtioe [Karolinska Institute]
Malignant Pleural Mesothelioma (MPM) is an asbestos induced aggressive and incurable cancer that originates in the pleural lining of the lung. MPM patients have a bleak outlook: life expectancy after diagnosis is 1-1.5 years. Genetic profiling of MPM tumours has unveiled a specific but limited set of common loss of function mutations, prominently mutations within the Hippo pathway members and in the deubiquitinase BAP1(1,2). In order for patients to obtain personalized treatment strategies, experimental models where the patients cancerous cells drug sensitivities can be evaluated needs to be scalable, represent the disease and be relatively fast in order to be clinical relevant. 2D cell culture lack some critical aspects of the disease. Mouse models partially recapitulate the hallmarks of MPM, but are slow, often exclusively provide end point insights, and are not adaptable to high through put pre-clinical studies. Consequently, novel mesothelioma models that recapitulate critical aspects of the disease and allow for high through put pre-clinical studies approaches in a clinical meaningful timeframe are needed. Zebrafish xenograft models have recently shown great promise to address both basic questions in tumor biology and metastasis, as a model for cancer compound screening (3,4). Recent translational studies using both stable cell lines and patient-derived xenografts have further supported the value of the zebrafish as a cancer model (3,4). In this project we will use transgenic zebrafish strains combined with patient derived mesothelioma cells and a recently developed isogenic mesothelioma cell model. Zebrafish larvae are transparent and thus allow for straight forward repeated sub cellular resolution imaging throughout the xenograft assay and are amenable to high-throughput functional and drug screening studies. This allows us to establish a zebrafish larval xenograft mesothelioma model which we will complement by using patient derived MPM cells to generate zebrafish avatars. The further development, implementation and indepth quantitative analysis of this xenograft pleural mesothelioma zebrafish larval model will be used to assess mesothelioma tumour-stroma interactions and reveal patient specific mesothelioma vulnerabilities that can be used therapeutically. Our experimental plan and multi-parametric analysis seek to reveal detailed interactions between the mesothelioma cells, the stroma and inflammatory cells. This workflow will pave the way for high throughput drug discovery and MPM patient specific precision therapy.
1: Develop a malignant pleural mesothelioma xenograft larval model compatible with high content screening
2: Characterise xenograft model using high content imaging including interplay between the cancerous mesothelioma cells, the stroma and inflammation
3: Obtain proteomics and transcriptomics analysis of micro tumours
4: Carry out genetic and drug screens in xenograft targeting candidates
The project includes in vivo and in vitro genome editing, high content and quantitative imaging, image analysis, compound in vivo screening, biochemistry, primary cell culture, proteomics and transcriptomics workflow, quantitative analysis and compound validation. The project provides training in MatLab, “R” and Python combined with diverse interdisciplinary techniques and model systems. The studentship includes research stays and workshops at Karolinska, which allows the candidate an international research experience. Combined, this safeguards that the candidate upon completion of the PhD will become an agile researcher with a timely, broad and unique skillset necessary for a successful career in Science. The candidate will join a collaborative, supportive and team-oriented research environment.
About the Programme
This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.
All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.
Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.
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