ABOVE: Cells can either be swallowed by other cells or invade other cells to create cell-in-cell events. ©istock, Rost-9D
The relationship between two cells can be complicated. They can exchange signals, stick to each other, or even compete for resources. However, in 2007, scientists at Harvard Medical School observed another curious phenomenon: cells could exist inside other cells.1
This wasn’t completely unprecedented: after all, scientists had long known about phagocytosis, a form of “cell cannibalism” where immune cells destroy damaged cells by chewing them up. But what the Harvard researchers saw was different. These cells weren’t getting swallowed in the same way: rather, they seemed to be invading 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, which were linked to worse cancer outcomes. Even as researchers continued to find more examples, however, cell-in-cell events remained an enigma. “We don't understand the origins or the physiology underlying the majority of these kinds 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. “Lots of people have looked at cell-in-cell phenomena, but mostly in individual organisms,” she said. “They haven’t really looked at it from the perspective of social evolution.”
In a recent study published in Scientific Reports, Kapsetaki and her colleagues at Arizona State University shed more light on cell-in-cell events by tracing their occurrences in different animals and microbes.2 Based on the associations of these events with many species and with genes that are millions of years old, the researchers proposed 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, while also cautioning against viewing them solely as harbingers of disease.
To compile a catalog of cell-in-cell events, Kapsetaki scoured 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 critical to normal processes in certain species. For example, in the tiny roundworm Caenorhabditis elegans, a cell involved in the development of reproductive organs is eaten alive by another cell to signal the final changes required for fertility.3 In mice, some maternal cells are engulfed by fetal cells as the embryo implants in the uterus.4
This confirmed what many in the field had suspected: cell-in-cell events are diverse and widespread. “If it can occur so easily, why wouldn't it be used in biology for lots of reasons?” said Overholtzer, who was not involved in this study.
Importantly, Kapsetaki even found examples of single-cell organisms engaging in cell-in-cell events, suggesting that these processes may have originated even before multicellular organisms first appeared. To confirm this, she estimated the ages of genes that previous studies had identified as drivers of cell-in-cell events. Some predated multicellular organisms by more than 1.5 billion years, a result that Overholtzer said gives scientists something new to consider. “These genes that control these behaviors are ancient,” he said.
Although Kapsetaki is unsure whether the genes actually promoted cell-in-cell events at that prehistoric time, she said it’s important to recognize the long history of these events as part of normal development, even though they were discovered in the context of cancer.
“If we want to make better cancer treatments, we have to carefully consider what’s happening with these cell-in-cell events,” she said. She is interested in further investigating this link by correlating cell-in-cell events and cancer across species, but noted that this requires better documentation of cell-in-cell events.
Overholtzer agreed that much is still unknown, but the findings of this study haven’t dissuaded him from studying 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, it's no different than anything you do to try 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 nonapoptotic 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 across the tree of life. Sci Rep. 2024;14(1):7535.
3. Lee Y, et al. Entosis controls a developmental cell clearance in C. elegans. Cell Rep. 2019;26(12):3212-3220.e4.
4. Li Y, et al. Entosis allows timely elimination of the luminal epithelial barrier for embryo implantation. Cell Rep. 2015;11(3):358-365.