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Cellular transformation by combined lineage conversion and oncogene expression

View ORCID ProfileBiswajyoti Sahu, View ORCID ProfilePäivi Pihlajamaa, Kaiyang Zhang, Kimmo Palin, Saija Ahonen, Alejandra Cervera, Ari Ristimäki, Lauri A. Aaltonen, View ORCID ProfileSampsa Hautaniemi, View ORCID ProfileJussi Taipale
doi: https://doi.org/10.1101/525600
Biswajyoti Sahu
1Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Finland
2Medicum, Faculty of Medicine, University of Helsinki, Finland
3Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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  • ORCID record for Biswajyoti Sahu
Päivi Pihlajamaa
1Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Finland
3Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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Kaiyang Zhang
4Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Finland
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Kimmo Palin
1Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Finland
2Medicum, Faculty of Medicine, University of Helsinki, Finland
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Saija Ahonen
1Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Finland
2Medicum, Faculty of Medicine, University of Helsinki, Finland
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Alejandra Cervera
4Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Finland
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Ari Ristimäki
1Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Finland
2Medicum, Faculty of Medicine, University of Helsinki, Finland
5Department of Pathology, HUSLAB, Helsinki University Hospital, University of Helsinki, Finland
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Lauri A. Aaltonen
1Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Finland
2Medicum, Faculty of Medicine, University of Helsinki, Finland
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Sampsa Hautaniemi
4Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Finland
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  • ORCID record for Sampsa Hautaniemi
Jussi Taipale
1Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Finland
3Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
6Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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  • For correspondence: ajt208@cam.ac.uk
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Abstract

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 Statement

The authors have declared no competing interest.

Footnotes

  • We have updated the title, revised Figures 4 and 5, and modified all the figures to have a total of six figures instead of four.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 23, 2020.
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Cellular transformation by combined lineage conversion and oncogene expression
Biswajyoti Sahu, Päivi Pihlajamaa, Kaiyang Zhang, Kimmo Palin, Saija Ahonen, Alejandra Cervera, Ari Ristimäki, Lauri A. Aaltonen, Sampsa Hautaniemi, Jussi Taipale
bioRxiv 525600; doi: https://doi.org/10.1101/525600
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Cellular transformation by combined lineage conversion and oncogene expression
Biswajyoti Sahu, Päivi Pihlajamaa, Kaiyang Zhang, Kimmo Palin, Saija Ahonen, Alejandra Cervera, Ari Ristimäki, Lauri A. Aaltonen, Sampsa Hautaniemi, Jussi Taipale
bioRxiv 525600; doi: https://doi.org/10.1101/525600

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