Human cell transformation by combined lineage conversion and oncogene expression

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http://hdl.handle.net/10138/334405

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Sahu , B , Pihlajamaa , P , Zhang , K , Palin , K , Ahonen , S , Cervera , A , Ristimäki , A , Aaltonen , L A , Hautaniemi , S & Taipale , J 2021 , ' Human cell transformation by combined lineage conversion and oncogene expression ' , Oncogene , vol. 40 , pp. 5533-5547 . https://doi.org/10.1038/s41388-021-01940-0

Titel: Human cell transformation by combined lineage conversion and oncogene expression
Författare: Sahu, Biswajyoti; Pihlajamaa, Päivi; Zhang, Kaiyang; Palin, Kimmo; Ahonen, Saija; Cervera, Alejandra; Ristimäki, Ari; Aaltonen, Lauri A.; Hautaniemi, Sampsa; Taipale, Jussi
Upphovmannens organisation: Department of Biochemistry and Developmental Biology
Digital Precision Cancer Medicine (iCAN)
ATG - Applied Tumor Genomics
Faculty of Medicine
University of Helsinki
Research Program in Systems Oncology
Sampsa Hautaniemi / Principal Investigator
Lauri Antti Aaltonen / Principal Investigator
Department of Medical and Clinical Genetics
Research Programs Unit
Department of Pathology
HUSLAB
Medicum
HUS Diagnostic Center
Helsinki University Hospital Area
Faculty Common Matters
Bioinformatics
Jussi Taipale / Principal Investigator
Datum: 2021-09-09
Språk: eng
Sidantal: 15
Tillhör serie: Oncogene
ISSN: 0950-9232
DOI: https://doi.org/10.1038/s41388-021-01940-0
Permanenta länken (URI): http://hdl.handle.net/10138/334405
Abstrakt: 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.
Subject: HEPATOCELLULAR-CARCINOMA
HUMAN FIBROBLASTS
RAS ONCOGENES
CANCER
TUMOR
GENES
MYC
METHYLATION
INDUCTION
TUMORIGENESIS
3122 Cancers
Referentgranskad: Ja
Licens: cc_by
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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