Metastasis—the ability of cancer cells to disperse throughout the body and establish new tumours at distant locations—is responsible for most cancer‐related deaths. Although both single and clusters of circulating tumour cells (CTCs) have been isolated from cancer patients, CTC clusters are generally associated with higher metastatic potential and worse prognosis. From an evolutionary perspective, being part of a cluster can provide cells with several benefits both in terms of survival (e.g. protection) and reproduction (group dispersal). Thus, strategies aimed at inducing cluster dissociation could decrease the metastatic potential of CTCs. However, finding agents or conditions that induce the dissociation of CTC clusters is hampered by the fact that their detection, isolation and propagation remain challenging. Here, we used a mechanistic agent‐based model to (a) investigate the response of CTC clusters of various sizes and densities to different challenges—in terms of cell survival and cluster stability, and (b) make predictions as to the combination of factors and parameter values that could decrease the fitness and metastatic potential of CTC clusters. Our model shows that the resilience and stability of CTC clusters are dependent on both their size and density. Also, CTC clusters of distinct sizes and densities respond differently to changes in resource availability, with high‐density clusters being least affected. In terms of responses to microenvironmental threats (such as drugs), increasing their intensity is, generally, least effective on high‐density clusters. Lastly, we found that combining various levels of resource availability and threat intensity can be more effective at decreasing the survival of CTC clusters than each factor alone. We suggest that the complex effects that cluster density and size showed on both the resilience and stability of the CTC clusters are likely to have significant consequences for their metastatic potential and responses to therapies.

中文翻译：

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基于代理的建模揭示了降低循环肿瘤细胞簇的适应性和转移潜力的策略。


转移——癌细胞扩散到全身并在远处形成新肿瘤的能力——是大多数癌症相关死亡的原因。尽管已从癌症患者体内分离出单个循环肿瘤细胞 (CTC) 和簇状循环肿瘤细胞 (CTC)，但 CTC 簇通常与较高的转移潜力和较差的预后相关。从进化的角度来看，成为簇的一部分可以为细胞在生存（例如保护）和繁殖（群体分散）方面提供多种好处。因此，旨在诱导簇解离的策略可以降低 CTC 的转移潜力。然而，由于 CTC 簇的检测、分离和传播仍然具有挑战性，因此寻找诱导 CTC 簇解离的试剂或条件受到阻碍。在这里，我们使用基于机械代理的模型来（a）研究不同大小和密度的 CTC 簇对不同挑战的响应（在细胞存活和簇稳定性方面），以及（b）对因素组合进行预测以及可能降低 CTC 簇的适应性和转移潜力的参数值。我们的模型表明，CTC 簇的弹性和稳定性取决于它们的大小和密度。此外，不同大小和密度的 CTC 集群对资源可用性变化的响应也不同，高密度集群受影响最小。就对微环境威胁（例如药物）的反应而言，增加其强度通常对高密度集群效果最差。最后，我们发现，将不同级别的资源可用性和威胁强度结合起来，比单独使用单个因素更能有效地降低 CTC 集群的生存率。 我们认为，簇密度和大小对 CTC 簇的弹性和稳定性所表现出的复杂影响可能对其转移潜力和对治疗的反应产生重大影响。