Patterns of Early p21 Dynamics Determine Proliferation-Senescence Cell Fate after Chemotherapy

Chemotherapy is designed to induce cell death. However, at non-lethal doses, cancer cells can choose to remain proliferative or become senescent. The slow development of senescence makes studying this decision challenging. Here, by analyzing single-cell p21 dynamics before, during, and days after drug treatment, we link three distinct patterns of early p21 dynamics to final cell fate. Surprisingly, while high p21 expression is classically associated with senescence, we find the opposite at early times during drug treatment: most senescence-fated cells express much lower p21 levels than proliferation-fated cells. We demonstrate that these dynamics lead to a p21 "Goldilocks zone" for proliferation, in which modest increases of p21 expression can lead to an undesirable increase of cancer cell proliferation. Our study identifies a counter-intuitive role for early p21 dynamics in the cell-fate decision and pinpoints a source of proliferative cancer cells that can emerge after exposure to non-lethal doses of chemotherapy.