TThe relationship between two cells can be complicated. They can exchange signals, stick together, or even compete for resources. But in 2007, scientists at Harvard Medical School observed another strange phenomenon: cells could exist inside other cells.1
This was not entirely unprecedented: after all, scientists had long known about phagocytosis, a form of “cellular cannibalism” in which immune cells destroy damaged cells by chewing them up. But what the Harvard researchers saw was different. These cells were not swallowed in the same way: Rather, they seemed to invade another cell. Once inside, they could actually survive.
This process, called entosis, seemed to explain the strange, nested cells that doctors sometimes saw in tumors and that were linked to worse cancer outcomes. But even as researchers found more examples, the cell-in-cell events remained a mystery. “We don’t understand the origins or the physiology underlying most of these types of events,” said Michael Overholtzer, a cell biologist at Memorial Sloan Kettering Cancer Center who co-authored the 2007 study.
When Stefania Kapsetaki, now a biologist at Tufts University, first heard about entosis, she was immediately intrigued. She had previously studied how cooperation between cells led to the evolution of multicellular organisms and hypothesized that similar forces might be at play in cell-in-cell events. “A lot of people have looked at cell-in-cell phenomena, but mostly in single organisms,” she said. “They haven’t really looked at it from the perspective of social evolution.”
In a recently published study Scientific reportsKapsetaki and her colleagues at Arizona State University have shed more light on cell-in-cell events by tracking their occurrence in various animals and microbes.2 Because of the associations of these events with many species and with genes that are millions of years old, the researchers suggested that cell-in-cell events may be an ancient and normal aspect of cellular interactions. This observation underscores the importance of studying these rare events, Kapsetaki said, but cautions against viewing them solely as harbingers of disease.
To compile a catalog of cell-in-cell events, Kapsetaki combed through decades of literature. She found many different types of these events: In some reports, both cells survived, while in others, the engulfed cell died. Some events involved cancer cells, others did not. Cell-in-cell events were crucial to normal processes in certain species. For example, in the tiny roundworm Caenorhabditis elegansa cell involved in the development of the reproductive organs is eaten alive by another cell in order to signal the final changes necessary for fertility.3 In mice, when the embryo implants in the uterus, some maternal cells are displaced by fetal cells.4
This confirmed what many in the field had suspected: cell-in-cell events are diverse and widespread. “If they can occur so easily, why not use them in biology for many reasons?” said Overholtzer, who was not involved in this study.
Importantly, Kapsetaki even found examples of single-celled organisms involved in cell-in-cell events, suggesting that these processes may have evolved before multicellular organisms first appeared. To confirm this, she estimated the age of genes identified in previous studies as drivers of cell-in-cell events. Some of them were more than 1.5 billion years older than multicellular organisms. A result that Overholtzer said gave scientists new ideas to consider. “These genes that control these behaviors are ancient,” he said.
Although Kapsetaki is not sure whether the genes actually promoted cell-in-cell events at this prehistoric time, she says it is important to recognize the long history of these events as part of normal development, even if they were discovered in the context of cancer.
“If we want to develop better cancer treatments, we need to think carefully about what happens in these cell-in-cell events,” she said. She is interested in studying this connection further by correlating cell-in-cell events and cancer across species, but noted that this will require better documentation of cell-in-cell events.
Overholtzer agreed that much remains unknown, but the results of this study have not deterred him from exploring entosis as a potential cancer drug target. He noted that many other processes targeted by cancer therapeutics, such as metabolism, cell growth and signaling, are also present in normal cells.
“To me, this is no different than anything you do to shrink a cancer,” Overholtzer said. “No matter what we do, there are cascading effects on the tissue. I don’t think cell-in-cell phenomena are necessarily any different. They should still be on the table.”
References
1. Overholtzer M, et al. A non-apoptotic cell death process, entosis, that occurs by cell-in-cell invasion. cell. 2007;131(5):966-979.
2. Kapsetaki SE, et al. Cell-in-cell phenomena throughout the tree of life. Scientific Representative. 2024;14(1):7535.
3. Lee Y, et al. Entosis controls developmental cell clearance in C.elegans. Cell Representative. 2019;26(12):3212-3220.e4.
4. Li Y, et al. Entosis enables timely removal of the luminal epithelial barrier for embryo implantation. Cell Representative. 2015;11(3):358-365.
