Agent‐based modelling reveals strategies to reduce the fitness and metastatic potential of circulating tumour cell clusters

Abstract

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.

Better together: circulating tumor cell clustering in metastatic cancer

“…Ongoing trials are seeking to reconcile and elucidate these findings by looking at correlations between chemotherapy treatment and disease subtype to better understand the effect on CTCs. However, in a model-based study of CTC clusters, clusters are more resistant to single-point attacks than single CTCs [ 87 ]. As such, CTC clusters are less likely to be impacted by chemotherapy treatment alone and instead will be more susceptible to combination attacks that reduce both their resources and increase their environmental threats.…”

“…As such, CTC clusters are less likely to be impacted by chemotherapy treatment alone and instead will be more susceptible to combination attacks that reduce both their resources and increase their environmental threats. The mentioned study also showed that high-density clusters are further protected from changes in resource availability or environmental threats, suggesting that, although these populations are rare, they are also extremely dangerous [ 87 ].…”

Spatial cumulant models enable spatially informed treatment strategies and analysis of local interactions in cancer systems

“…Such perturbations can lead to reduced tumour growths and disease burdens (Zhang et al, 2017; Dominiak et al, 2020; Brücher and Jamall, 2014; West and Newton, 2019). Cell-cell interactions, and the impact that they have on cancer system dynamics, have been mathematically studied by researchers using a variety of mathematical models including evolutionary game theory (EGT) models (Zhang et al, 2017; Kaznatcheev et al, 2019; Archetti et al, 2015), other ordinary differential equation (ODE) models (Hillen et al, 2013; Poleszczuk and Enderling, 2018; Jenner et al, 2018), partial differential equation (PDE) models (Haridas et al, 2017; Lorenzi et al, 2017; Hinow et al, 2009), and individual-based models (IMBs) (Stichel et al, 2017; Campenni et al, 2020; Hamis et al, 2021).…”

Density Regulation and Localization of Cell Clusters by Self-Assembled Femtosecond-Laser-Fabricated Micropillar Arrays

“…Cancer metastasis is a major cause of cancer-related mortality. Compared to single cancer cells, tumor cell clusters have shown higher metastasis initiation capability. , Accordingly, dynamic analysis of tumor cell clusters is important for understanding how the metastatic potential of cancer might be reduced. Within a cluster, cellular plasticity and strong cell–cell connections confer higher cellular survival rates, greater proliferation, and resistance. − Tumor cell clusters of various sizes and densities respond differently to resources or environmental changes, and cell survival and cluster stability under different conditions vary dramatically .…”

“…Within a cluster, cellular plasticity and strong cell–cell connections confer higher cellular survival rates, greater proliferation, and resistance. − Tumor cell clusters of various sizes and densities respond differently to resources or environmental changes, and cell survival and cluster stability under different conditions vary dramatically . Therefore, the controlled generation of cell clusters of varying sizes and densities would allow a better understanding of the differences in metastatic potential among clusters . Although considerable research has been focused on the cluster size, − the responses of clusters of different densities to particular conditions are still unknown.…”