Liver and brain organoids to model human pluripotent stem cell tumorigenesis
Dr. Diana Al Delbany, Dr. Manjusha Ghosh
An important concern in the clinical translation of hPSC cells is their potential for tumour formation. Up to now, research has focused on the possibility that poorly differentiated or progenitor cells initiate tumour formation upon transplantation. Conversely, hPSC are prone to acquiring genetic abnormalities that are very similar to those identified in cancers and there is virtually no knowledge on whether these can prime the cells for oncogenic transformation. This gap in knowledge is for the most part due to a lack of suitable research models and systematic studies. In this project, we propose that these mutations represent a first hit in the oncogenic process, making these cells one step closer to becoming cancerogenic. We will develop novel organoid-based models of in vitro brain and liver cancer, which we will use to study if specific genetic abnormalities enhance the tumorigenic potential of hPSC-derived cells. We will use our collection of hPSC lines with well characterized genetic abnormalities to generate liver and brain organoids and subject the organoids to directed mutagenesis to speed up the tumorigenic process. This will allow us to study if genetically abnormal hPSC require less or different mutations to undergo transformation than their genetically normal counterparts. This study will provide, for the first time, insight on the long-term risks of transplanting hPSC-derived cells carrying genetic abnormalities.