TThe relationship between the two cells is complex: they exchange signals, stick to each other, and even compete for resources. But in 2007, scientists at Harvard Medical School observed another intriguing phenomenon. Cells may exist within other cells.1
This isn’t an entirely unprecedented phenomenon: Scientists have long known about phagocytosis, a form of “cell cannibalism” in which immune cells chew up and destroy damaged cells. But what the Harvard researchers saw was different: Rather than being engulfed in the same way, these cells seemed to invade other cells. And once inside, the cells were actually able to survive.
This process, called entosis, seemed to explain the strange nested cells doctors sometimes see in tumors, which have been linked to worse cancer outcomes. But even as researchers continued to find more examples, the intracellular events remained a mystery. “We don’t understand the origin or underlying physiology of the vast majority of these types of events,” he said. Michael OberholtzerHe is a cell biologist at Memorial Sloan Kettering Cancer Center and co-author of the 2007 study.
when Stefania KapsetakiWhen she first heard about entosis, now a biologist at Tufts University, 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 work in intracellular events. “A lot of people have looked at intracellular events, but mostly at individual organisms,” she says. “Not many have looked at it from a social evolutionary perspective.”
In a recently published study, Scientific ReportsDr. Kapsetaki and her colleagues at Arizona State University looked more closely at the intracellular events. Outbreak tracking In various animals and microorganisms.2 Because these phenomena are associated with many species and genes that are millions of years old, the researchers proposed that the intracellular phenomena may be an ancient and normal aspect of cell interactions. Kapsetaki said the observations highlight the importance of studying these rare phenomena, but also caution against viewing them simply as precursors to disease.
Kapsetaki combed through decades of literature to create a catalog of intracellular events. 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, while others did not. The intracellular events were essential for normal processes in certain species. For example, Inside a tiny roundworm NematodesA cell involved in the development of reproductive organs is eaten alive by another cell, signaling the final changes required for reproduction.3 In mice, Maternal cells are engulfed by fetal cells As the fertilized egg implants in the uterus.4
This confirmed what many in the field had suspected: The events in cells are diverse and widespread. “If it’s so simple, why wouldn’t it be exploited in biology for a variety of reasons?” says Oberholtzer, who was not involved in the study.
Importantly, Kapsetaki even found examples of single-celled organisms carrying out intracellular events, suggesting that these processes may have begun before multicellular organisms first emerged. To support this, she estimated the ages of genes that previous studies had identified as driving intracellular events; some are more than 1.5 billion years older than multicellular organisms, a result that Oberholtzer says gives scientists new insights. “The genes that control these behaviors are ancient,” he said.
Kapsetaki says he can’t be sure that these genes actually drove prehistoric events in cells, but that it’s important to recognize the long history of these events as part of normal development, even if they’ve been discovered in the context of cancer.
“If we want to develop better cancer treatments, we need to carefully consider what is happening in these intracellular events,” she said. She is interested in exploring this association further by correlating intracellular events with cancer across species, but noted that this requires better documentation of intracellular events.
Oberholtzer agreed that much remains unknown, but the findings haven’t stopped him from investigating entosis as a potential cancer drug target. He noted that many of the other processes that cancer drugs target, such as metabolism, cell proliferation and signaling, also exist in normal cells.
“To me, this is no different than anything else you do to shrink a cancer,” Oberholtzer said. “Whatever you do has a cascading effect on the tissue. I don’t think that intracellular cellular events are necessarily different. It’s still something to consider.”
References
1. Overholtzer M, et al. Entosis, a non-apoptotic cell death process triggered by intracellular invasion. cell2007;131(5):966-979.
2. Kapsetaki SE et al. Subcellular phenomena in the tree of life. Scientific Reports2024;14(1):7535.
3. Lee Y, et al. Entosis controls cell clearance during development Nematodes. Cellrep.2019;26(12):3212-3220.e4.
4. Li Y, et al. Entosis allows for the timely removal of the luminal epithelial barrier necessary for embryo implantation. Cellrep2015;11(3):358-365.
