Cancer is the second leading cause of death worldwide, according to the World Health Organization. Most cancer deaths are due to metastasis, in which cancer cells break off from the original tumor and develop new tumors in other parts of the body.

While cancer patients may have single or clusters of circulating tumor cells (CTCs), CTC clusters are commonly linked to greater chances of metastasis and worse prognosis. Cells in CTC clusters may have survival and reproductive advantages, such as through greater protection and dispersing in clusters rather than single cells. Yet much is still unknown about CTC cluster biology or strategies to impede their metastatic potential.

Researchers, including Amy Boddy, an assistant professor in UC Santa Barbara’s Department of Anthropology, investigated different CTC cluster factors and environmental conditions that could decrease their fitness and metastatic potential. Published in Evolutionary Applications, their study is part of the work being done by the Arizona Cancer and Evolution Center consortium, of which UCSB is a participant.

“Our group studies cancer from an evolutionary and ecological perspective, so we’re looking at maybe a broader theoretical framework of studying cancer cell dynamics,” Boddy said. “We know a lot of ecological dynamics. So if we can take them and make predictions to apply this to cancer cells, we might be able to think of novel ways of treating or thinking about how to study cancer.”

The researchers used mechanistic computational modeling to examine how CTC clusters of four different sizes and of varying densities — high, medium and low — could respond to certain conditions.

“A lot of the literature currently on cancer cell clusters is looking at size … but the connections within the cells matter, too. So not only are we looking at cancer cell cluster size, but we wanted to look at the density of the clusters, how many neighbors are connected to each individual cell as well,” Boddy described.

(a) Examples of different cancer types with varying shapes, densities and cell numbers. (b) Clusters from two lung cancer cell lines, displaying differences in cluster density. (c) Simulated clusters that were used in the model. Courtesy of Amy Boddy

Boddy and her colleagues studied how clusters of different sizes and densities would fare when facing different levels of environmental threats, which they called “microenvironmental threats.” These challenges included varying resource availability and factors such as the immune system, chemotherapies or drugs.

The scientists then measured the outcomes of cell survivability (also defined as resilience) and stability of the CTC clusters.

“What we found was that, actually, density matters a lot,” Boddy said. 

“If we had very large clusters that weren’t extremely dense, then they were still able to dissociate and died in the model. But these strongly dense clusters, no matter small or large, were much more resilient to whatever we threw at it in the model.”

Highly dense clusters were the least affected by low resource availability or environmental challenges. They were more resilient than lower-density clusters, regardless of cluster size or threat level. 

Cluster size played a smaller but still significant role in survivability against threats for medium-density and low-density clusters. Larger clusters were generally more resilient than smaller ones.

In examining stability, cluster density mattered, but not size. Highly dense clusters had a higher survival rate and greater stability, making them more difficult to dissociate compared to same-size clusters with lower density, according to the paper.

Boddy noted, “The takeaway is that we should not only be measuring the size of the cellular clusters but also the density.”

The team found that using a combination of threat and reduced resource availability could be more effective at decreasing the survival rates of CTC clusters than applying each factor individually.

“This is extremely important for [high-density] clusters, which tend to be more resilient and more stable than [medium-density] and [low-density] clusters, irrespective of size,” the authors wrote.

As the study was carried out using simulated models, Boddy mentioned the “big caveat” is that these findings should be further tested, such as in cellular cultures (in vitro) and in mouse models (in vivo).

With in vitro and in vivo testing of these findings, “more individualized therapies directed at decreasing the metastatic potential of specific CTC cluster types with fewer side effects” may be developed to help increase clinical outcomes for cancer patients, the paper states.

“If there are drugs that disassociate the clusters, we need to be concerned that we are not disassociating these large, dense clusters because then we are just going to have a lot more small, dense clusters,” Boddy remarked. “And so, maybe new targeting therapeutics that break down the density of the cell clusters is something that could be looked at as a future therapy, to target the absolute density of the cluster.”

The researchers are continuing to use modeling, with some collaborators working with cell cultures.

“[They are] looking at the ecological parameters of cell cluster density in a cell culture setting … and trying to disassociate the actual density of them,” Boddy said. 

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