Intercellular heterogeneity of the p53 transcriptional response to oncogenic stress

We use scRNA-seq to investigate the intercellular heterogeneity of the p53 transcriptional response to oncogenic stress. Comparisons of the transcriptomes of cells collected in the absence and in the presence of p53 activation revealed the expected upregulation of direct p53 target genes as well as the downregulation of E2F- and Myc-target genes, previously indirectly linked to the p53 pathway. Strikingly, the majority of previously defined p53 core target genes were induced in only a fraction of the cells. In addition, we identified two distinct subsets of cells within the p53-responsive group, differentiated by their expression of proliferative and metabolic signatures. While one group was characterized by gene expression changes consistent with a robust halt in cell cycle progression, the second group exhibited a strong activation of genes linked to oxidative phosphorylation. Inhibition of oxidative phosphorylation impaired the ability of cells to undergo p53-induced senescence, highlighting the importance of this pathway in mediating p53 tumor suppressive functions. scRNA-seq profiles of lung adenocarcinoma (LA2) cells from the p53-restorable K-rasLA2; p53LSL/LSL; Rosa26-CreERT2 (KPR) mouse model, untreated or treated with 4-hydroxytamoxifen (4-OHT) for 16h