Key points are not available for this paper at this time.
We generated two mouse models, p21 +/Tert and p21 +/TertCi , expressing either telomerase reverse transcriptase (Tert) or a catalytically inactive variant under the control of the p21 promoter. By 18–20 mo of age, ∼15% of mice from both genotypes developed liver tumors with histopathological features resembling human hepatocellular carcinoma (HCC). Whole-exome sequencing identified activating Ctnnb1 mutations and recurrent PP1 subunit alterations in p21 +/Tert tumors, whereas p21 +/TertCi tumors harbored activating Hras Gln61Lys mutations associated with elevated C > A transversions. Both models exhibited chromosomal aberrations commonly observed in human HCC. Transcriptomic analyses revealed that β-catenin–activated tumors recapitulated gene expression signatures of human HCC, whereas MAPK-mutated tumors showed profiles consistent with MAPK/ERK pathway activation. All HCCs suppressed the gluconeogenic genes Fbp1 and AldoB , but diverged into two distinct groups based on their glycolytic and NRF2 target gene expression profiles. Spatial profiling further revealed reduced HNF4α-positive hepatocytes across tumors, independent of HNF4α transcription, and markedly diminished immune cell infiltration, particularly in β-catenin–activated tumors. Collectively, these findings uncover telomere-independent functions of Tert and identify molecular and metabolic features with potential relevance for predicting immunotherapy response.
Braud et al. (Fri,) studied this question.