Titration of RAS alters senescent state and influences tumour initiation
Adelyne S L Chan1, Haoran Zhu1, Masako Narita1
1Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
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.
Insights
Oncogenic RAS-induced senescence (OIS) normally suppresses tumors. However, lower oncogenic RAS dosage allows immune escape, leading to distinct hepatocellular carcinoma types, revealing a spectrum of OIS phenotypes.
Area of Science:
- Molecular Biology
- Oncology
- Immunology
Background:
- Oncogenic RAS-induced senescence (OIS) is a tumor suppressor mechanism during premalignancy.
- The impact of lower oncogenic RAS dosage on OIS phenotypes and tumor initiation is not well understood.
Purpose of the Study:
- To investigate the spectrum of OIS phenotypes driven by varying oncogenic RAS dosages.
- To elucidate the mechanisms of immune evasion and tumor development under different oncogenic stress levels.
Main Methods:
- Development of in vitro and in vivo oncogenic RAS dose-escalation models.
- Single-cell RNA sequencing to analyze hepatocyte subpopulations.
- Time-series monitoring at single-cell resolution to track tumor development.
Main Results:
- A non-linear continuum of downstream phenotypes was observed with escalating oncogenic RAS dosage.
- Lower NRAS(G12V) dosage resulted in immune-resistant hepatocytes and tumor formation.
- Two distinct hepatocellular carcinoma subtypes (early-onset aggressive undifferentiated and late-onset differentiated) were identified, linked to progenitor features and human HCC subclasses.
Conclusions:
- Oncogenic RAS dosage critically influences the OIS spectrum, determining tumor suppressor function or tumor initiation.
- Understanding the oncogenic dosage-driven OIS spectrum reconciles senescence and tumor initiation phenotypes in early tumorigenesis.
- This study provides insights into the heterogeneity of hepatocellular carcinoma development.
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