Published June 17, 2022 | Version v1
Journal article Open

Cellular transformation by combined lineage conversion and oncogene expression

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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.

Notes

JT was supported by grants from Academy of Finland (Finnish Center of Excellence in Tumor Genetics Research 2018-2025, grant number 312042 and 2012-2017; 250345), Finnish Cancer Foundation, and Cancer Research UK (grant number RG99643). BS was supported by the Academy of Finland (post-doctoral fellowship, 274555; research fellowship, 317807), Finnish Cancer Foundation, Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation and iCAN Digital Precision Cancer Medicine Flagship. PP was supported by the post-doctoral fellowship 288836 from Academy of Finland. AR was supported by Finska Läkaresällskapet, Helsinki University Central Hospital Research Funds, and Sigrid Jusélius Foundation. LA was supported by Academy of Finland (grant numbers 312041, 335823, 250345, 319083, 320149), iCAN Digital Precision Cancer Medicine Flagship (grant number 320185), Finnish Cancer Foundation, Sigrid Jusélius Foundation and Jane and Aatos Erkko Foundation. SH was supported by the European Union's Horizon 2020 research and innovation programme under Grant Agreement No. 667403 for HERCULES.

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Preprint: 10.1101/525600 (DOI)

Funding

Center of Excellence in Tumor Genetics Research / Consortium: CoETG 312041
Academy of Finland
Center of Excellence in Tumor Genetics Research / Consortium: CoETG 335823
Academy of Finland
Reprogramming normal cells to tissue-specific cancer by defined oncogenic factors 274555
Academy of Finland
HERCULES – Comprehensive characterization and effective combinatorial targeting of high-grade serous ovarian cancer via single-cell analysis 667403
European Commission
Towards understanding neoplasia through unique materials and data integration 319083
Academy of Finland
Finnish Center of Excellence in Cancer Genetics Research 250345
Academy of Finland
iCAN – The Digital Precision Cancer Medicine Platform 320185
Academy of Finland
Lineage-specific transcription factors and oncogenic reprogramming of enhancer landscape in genesis of cancer 317807
Academy of Finland
Towards understanding neoplasia through unique materials and data integration 320149
Academy of Finland