能源景观可以直观地描述人口异质性和动态。然而，目前尚不清楚假设由初始位置和噪声决定的个体细胞行为是否如实再现。使用乳腺癌休眠中 p21-/Cdk2 依赖性静止增殖决定作为试验台，我们检查了当受到缺氧（一种休眠诱导应激）干扰时单细胞的动态。将基于轨迹的能量景观生成与单细胞延时显微镜相结合，我们发现需要结合 p21/Cdk2 景观上的初始位置和速度，而不是单独的位置来解释缺氧下观察到的细胞命运异质性。这可能是由于额外的细胞状态信息，例如表观遗传特征和/或以速度编码的其他物种，但在仅由 p21 和 Cdk2 水平确定的瞬时位置中缺失。在这里，速度依赖性表现为惯性：缺氧前具有较高细胞周期速度的细胞在缺氧下继续沿细胞周期前进，抵抗细胞周期退出的景观变化。这种惯性效应可能会显着影响肿瘤和其他动态变化的微环境中的细胞命运轨迹，其中细胞状态转换由多个生化物种之间的协调控制。© 2024。作者。

Energy landscapes can provide intuitive depictions of population heterogeneity and dynamics. However, it is unclear whether individual cell behavior, hypothesized to be determined by initial position and noise, is faithfully recapitulated. Using the p21-/Cdk2-dependent quiescence-proliferation decision in breast cancer dormancy as a testbed, we examined single-cell dynamics on the landscape when perturbed by hypoxia, a dormancy-inducing stress. Combining trajectory-based energy landscape generation with single-cell time-lapse microscopy, we found that a combination of initial position and velocity on a p21/Cdk2 landscape, but not position alone, was required to explain the observed cell fate heterogeneity under hypoxia. This is likely due to additional cell state information such as epigenetic features and/or other species encoded in velocity but missing in instantaneous position determined by p21 and Cdk2 levels alone. Here, velocity dependence manifested as inertia: cells with higher cell cycle velocities prior to hypoxia continued progressing along the cell cycle under hypoxia, resisting the change in landscape towards cell cycle exit. Such inertial effects may markedly influence cell fate trajectories in tumors and other dynamically changing microenvironments where cell state transitions are governed by coordination across several biochemical species.© 2024. The Author(s).