Titration of RAS alters senescent state and influences tumour initiation

Adelyne S. L. Chan, Haoran Zhu, Masako Narita, Liam D. Cassidy, Andrew R. J. Young, Camino Bermejo-Rodriguez, Aleksandra T. Janowska, Hung-Chang Chen, Sarah Gough, Naoki Oshimori, Lars Zender, Sarah J. Aitken, Matthew Hoare and Masashi Narita ()
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Adelyne S. L. Chan: University of Cambridge
Haoran Zhu: University of Cambridge
Masako Narita: University of Cambridge
Liam D. Cassidy: University of Cambridge
Andrew R. J. Young: University of Cambridge
Camino Bermejo-Rodriguez: University of Liverpool
Aleksandra T. Janowska: University of Cambridge
Hung-Chang Chen: University of Cambridge
Sarah Gough: University of Cambridge
Naoki Oshimori: Oregon Health and Science University
Lars Zender: University Hospital Tuebingen
Sarah J. Aitken: University of Cambridge
Matthew Hoare: University of Cambridge
Masashi Narita: University of Cambridge

Nature, 2024, vol. 633, issue 8030, 678-685

Abstract: Abstract Oncogenic RAS-induced senescence (OIS) is an autonomous tumour suppressor mechanism associated with premalignancy1,2. Achieving this phenotype typically requires a high level of oncogenic stress, yet the phenotype provoked by lower oncogenic dosage remains unclear. Here we develop oncogenic RAS dose-escalation models in vitro and in vivo, revealing a RAS dose-driven non-linear continuum of downstream phenotypes. In a hepatocyte OIS model in vivo, ectopic expression of NRAS(G12V) does not induce tumours, in part owing to OIS-driven immune clearance3. Single-cell RNA sequencing analyses reveal distinct hepatocyte clusters with typical OIS or progenitor-like features, corresponding to high and intermediate levels of NRAS(G12V), respectively. When titred down, NRAS(G12V)-expressing hepatocytes become immune resistant and develop tumours. Time-series monitoring at single-cell resolution identifies two distinct tumour types: early-onset aggressive undifferentiated and late-onset differentiated hepatocellular carcinoma. The molecular signature of each mouse tumour type is associated with different progenitor features and enriched in distinct human hepatocellular carcinoma subclasses. Our results define the oncogenic dosage-driven OIS spectrum, reconciling the senescence and tumour initiation phenotypes in early tumorigenesis.

Date: 2024
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DOI: 10.1038/s41586-024-07797-z

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