Heritable tumor cell division rate heterogeneity induces clonal dominance

Tumors consist of a hierarchical population of cells that differ in their phenotype and genotype. This hierarchical organization of cells means that a few clones (i.e., cells and several generations of offspring) are abundant while most are rare, which is called clonal dominance. Such dominance also occurred in published in vitro iterated growth and passage experiments with tumor cells in which genetic barcodes were used for lineage tracing. A potential source for such heterogeneity is that dominant clones derive from cancer stem cells with an unlimited self-renewal capacity. Furthermore, ongoing evolution and selection within the growing population may also induce clonal dominance. To understand how clonal dominance developed in the iterated growth and passage experiments, we built a computational model that accurately simulates these experiments. The model simulations reproduced the clonal dominance that developed in in vitro iterated growth and passage experiments when the division rates vary between cells, due to a combination of initial variation and of ongoing mutational processes. In contrast, the experimental results can neither be reproduced with a model that considers random growth and passage, nor with a model based on cancer stem cells. Altogether, our model suggests that in vitro clonal dominance develops due to selection of fast-dividing clones.

肿瘤是一类具有层级结构的细胞群体，不同细胞的表型与基因型均存在差异。这种细胞层级组织结构意味着，少数克隆（即单个细胞及其数代子代细胞）数量占优，而绝大多数克隆数量稀少，该现象被称为克隆优势（clonal dominance）。此类克隆优势现象也曾出现在已发表的肿瘤细胞体外连续传代培养实验中，该类实验通过遗传条形码（genetic barcodes）进行谱系追踪。造成这种细胞异质性的潜在原因之一是，占优克隆源自具备无限自我更新能力的癌症干细胞（cancer stem cells）。此外，增殖群体内部持续发生的进化与选择过程同样可能诱导克隆优势。为探明该类体外连续传代培养实验中克隆优势的形成机制，我们构建了可精准复现该类实验的计算模型。当细胞分裂速率存在差异时——该差异由初始细胞异质性与持续发生的突变过程共同导致——该模型的模拟结果可复现体外连续传代培养实验中出现的克隆优势。与之相反，仅考虑随机生长与传代过程的模型，或是基于癌症干细胞的模型，均无法复现该实验结果。综上，我们的模型表明，体外实验中的克隆优势源于快速增殖克隆的选择效应。