Zebrafish models for precision medicine in mesothelioma

Malignant Pleural Mesothelioma (MPM) is an aggressive, infiltrative and incurable cancer that originates from the mesothelioma cell in the pleural lining of the lung lungs. Majority of the cases are associated with the exposure to the carcinogen asbestos. Unfortunately, there is currently no effective treatment for this disease. Patients with MPM have a bleak outlook with generally only 1-1.5 years survival after diagnosis . 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 .
MPM is an infiltrative cancer with widespread interactions with the stroma. 2D cell models lack insights into this tumour microenvironment. Thus, we decided to use animal model -zebrafish larvae Xenograft which enable us to simultaneously study mutations/genetic alteration in cell lines and animal model. Zebrafish xenografts are powerful preclinical model in a timeframe that is clinically relevant, scalable, relatively cheap, and readily available for imaging, and with potential for drug screening.
At the beginning I aim to develop a malignant pleural mesothelioma xenograft larval model compatible with high content screening by injecting a recently developed isogenic mesothelioma cellular model engineered to not express the tumour suppressors NF2 and BAP1. These larvae xenografts will be characterized using high content imaging with a focus on establishing new therapeutic relevant insights into the interplay between the cancerous mesothelioma cells, the stroma and inflammation. This will enable us to gain discover how cancer cells with different mutational profile differ in their ability to infiltrate and migrate in vivo.
Micro tumours will be dissected and FACS sorted for further analysis, including in-depth pathway analysis, to identify the most relevant genes and their interaction partners. After establishing the full protocol, I will use patient derived mesothelioma cells to develop zebrafish avatars and carry out candidate genetic and drug target exploration, in order to develop stratified precision medicine approaches.

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