RT Journal Article
SR Electronic
T1 Cellular transformation by combined lineage conversion and oncogene expression
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 525600
DO 10.1101/525600
A1 Biswajyoti Sahu
A1 Päivi Pihlajamaa
A1 Kaiyang Zhang
A1 Kimmo Palin
A1 Saija Ahonen
A1 Alejandra Cervera
A1 Ari Ristimäki
A1 Lauri A. Aaltonen
A1 Sampsa Hautaniemi
A1 Jussi Taipale
YR 2020
UL http://biorxiv.org/content/early/2020/05/23/525600.abstract
AB Cancer is the most complex genetic disease known, with mutations implicated in more than 250 genes. However, it is still elusive which specific mutations found in human patients lead to tumorigenesis. Here we show that a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT, MYC) induces senescence in human fibroblasts and primary hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps), makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. These results show that tumorigenesis is triggered by a combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Our results provide direct support for the role of cell identity as a key determinant in transformation, and establish a paradigm for studying the dynamic role of oncogenic drivers in human tumorigenesis.Competing Interest StatementThe authors have declared no competing interest.