Direct conversion of human fibroblasts to liver cancer cells

Abstract

Cancer is the most complex genetic disease known, with mutations in more than 250 genes contributing to different forms of the disease. Most mutations are specific to particular types of cancer, suggesting that cancer genes interact with cell lineage-determining factors to drive the transformation process. To identify the factors necessary and sufficient to define a lineage-specific cancer type, we have reprogrammed and transformed normal human fibroblasts to liver cancer cells. We show that reprogramming human fibroblasts to induced hepatocytes (iHeps) makes the cells sensitive to transformation by a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT and MYC). The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. Our results show that lineage-determining factors collaborate with oncogenes to drive tumorigenesis and establish a paradigm for defining the molecular states of distinct types of human cancer.