Generations in Flux: Tracking the Birth of Cellular Heterogeneity in Cancer

Intratumor heterogeneity is a hallmark of cancer, enabling subpopulations of cells to evade therapy, adapt to immune attack, and thrive in diverse microenvironments. While retrospective genomic and epigenomic analyses have mapped the large-scale histories of tumor evolution, they cannot capture the rapid, dynamic changes in cell state that occur as individual cells divide. Panagopoulos and colleagues recently developed a cellular platform to monitor the role of transient replication stress in real time, tracking sister cells as they divide and replicate. The authors use these techniques to show that daughter and granddaughter cells can inherit very different states, often leading to further cellular instability. This work broadens our understanding of how diverse cell states arise from oncogenic stress and how cellular heterogeneity emerges.