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Project
Liver and brain organoids to model human pluripotent stem cell tumorigenesis (FWOAL1071)
An important concern in the clinical translation of human pluripotent
stem cell-derived (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
stem cell-derived (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
Date:1 Jan 2023 → Today
Keywords:human pluripotent stem cell-derived organoids as cancer models, aneuploidy in early oncogenesis, copy number variants as a first hit in the oncogenic transformation of stem-cell derived cells
Disciplines:Cancer biology, Genetics, Stem cell biology