Department of Basic Science, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.
Research Center for Complex Systems Biology, The University of Tokyo, Tokyo, Japan.
PLoS One. 2021 Feb 1;16(2):e0236534. doi: 10.1371/journal.pone.0236534. eCollection 2021.
Cancer cell populations consist of phenotypically heterogeneous cells. Growing evidence suggests that pre-existing phenotypic differences among cancer cells correlate with differential susceptibility to anticancer drugs and eventually lead to a relapse. Such phenotypic differences can arise not only externally driven by the environmental heterogeneity around individual cells but also internally by the intrinsic fluctuation of cells. However, the quantitative characteristics of intrinsic phenotypic heterogeneity emerging even under constant environments and their relevance to drug susceptibility remain elusive. Here we employed a microfluidic device, mammalian mother machine, for studying the intrinsic heterogeneity of growth dynamics of mouse lymphocytic leukemia cells (L1210) across tens of generations. The generation time of this cancer cell line had a distribution with a long tail and a heritability across generations. We determined that a minority of cell lineages exist in a slow-cycling state for multiple generations. These slow-cycling cell lineages had a higher chance of survival than the fast-cycling lineages under continuous exposure to the anticancer drug Mitomycin C. This result suggests that heritable heterogeneity in cancer cells' growth in a population influences their susceptibility to anticancer drugs.
癌细胞群体由表型异质的细胞组成。越来越多的证据表明，癌细胞之间预先存在的表型差异与对抗癌药物的不同敏感性相关，并最终导致复发。这种表型差异不仅可以由细胞周围环境的异质性外部驱动，也可以由细胞内在的波动内部驱动。然而，在恒定的环境下，内在表型异质性出现的定量特征及其与药物敏感性的相关性仍然难以捉摸。在这里，我们使用微流控设备哺乳动物母机研究了数十代小鼠淋巴细胞白血病细胞 (L1210) 生长动力学的内在异质性。该癌细胞系的代时分布具有长尾和跨代遗传。我们确定少数细胞谱系在多个代时处于缓慢循环状态。与连续暴露于抗癌药物丝裂霉素 C 相比，这些缓慢循环的细胞谱系在持续暴露于抗癌药物丝裂霉素 C 时具有更高的存活机会。这一结果表明，癌细胞群体中生长的遗传性异质性会影响其对抗癌药物的敏感性。
