Cell-to-cell variability in Myc dynamics drives transcriptional heterogeneity in cancer cells

Cell-to-cell heterogeneity is vital for tumor evolution and survival. How cancer cells achieve and exploit this heterogeneity remains an active area of research. Here, we identify c-Myc as a highly heterogeneously expressed transcription factor and an orchestrator of transcriptional and phenotypic diversity in cancer cells. By monitoring endogenous c-Myc protein in individual living cells, we report the surprising pulsatile nature of c-Myc expression and the extensive cell-to-cell variability in its dynamics. We further show that heterogeneity in c-Myc dynamics leads to variable target gene transcription and that timing of c-Myc expression predicts cell-cycle progression rates and drug sensitivities. Together, our data advocate for a model in which cancer cells increase the heterogeneity of functionally diverse transcription factors such as c-Myc to rapidly survey transcriptional landscapes and survive stress.

Automated summary

Cell-to-cell heterogeneity is crucial for tumor evolution and survival, and cancer cells achieve this heterogeneity by expressing the highly heterogeneous transcription factor c-Myc. We have discovered that the expression of c-Myc displays a pulsatile nature and exhibits extensive cell-to-cell variability. This heterogeneity in c-Myc dynamics leads to variable transcription of target genes, and the timing of c-Myc expression predicts cell-cycle progression rates and drug sensitivities. Our findings suggest that cancer cells increase the heterogeneity of transcription factors, such as c-Myc, to adapt to stress and rapidly explore transcriptional landscapes.