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In a new review paper, Carlo Maley and colleagues at Arizona State University describe cell-to-cell phenomena in which one cell engulfs and sometimes engulfs another. The study shows that instances of this behavior, including cell cannibalism, are widespread across the tree of life.

The findings challenge the common belief that cell-to-cell events are largely confined to cancer cells. Rather, these events appear to be common in a variety of organisms, from single-celled amoebae to complex multicellular animals.

The widespread occurrence of such interactions in non-cancerous cells suggests that these events are not inherently “selfish” or “cancerous” behaviors. Rather, the researchers suggest that cell-to-cell phenomena may play a crucial role in normal development, homeostasis, and stress response in a wide range of organisms.

The study argues that targeting cell-to-cell events as a cancer treatment approach should be abandoned because these phenomena are not unique to malignancies.

By demonstrating that the events span a wide range of life forms and are deeply rooted in our genetic makeup, the research invites us to reexamine basic concepts of cellular cooperation, competition, and the complex nature of multicellularity. The study opens new avenues for research in evolutionary biology, oncology and regenerative medicine.

The study, published in Scientific reports, was the first to systematically investigate cell-by-cell phenomena in the tree of life. The group’s findings could help redefine the understanding of cellular behavior and its implications for multicellularity, cancer and the evolutionary journey of life itself.

“We first got into this work because we learned that cells don’t just compete for resources—they actively kill and eat each other,” says Maley. “This is a fascinating aspect of the ecology of cancer cells. But further investigation revealed that these phenomena occur in normal cells, and sometimes not a single cell dies, resulting in an entirely new type of hybrid cell.”

Mali is a researcher at the Biodesign Center for Biocomputing, Security and Society; professor in the School of Natural Sciences at ASU; and director of the Arizona Center for Cancer Evolution.

The study was conducted in collaboration with first author Stefania E. Kapsetaki, formerly of ASU and now a researcher at Tufts University, and Luis Cisneros, formerly of ASU and currently a researcher at the Mayo Clinic.

From selfish to cooperative cellular interactions

Cell-to-cell events have long been observed but remain poorly understood, especially outside the context of immune responses or cancer. The earliest genes responsible for cell-to-cell behavior date back more than 2 billion years, suggesting that the phenomenon plays an important, if still undefined, role in living organisms. Understanding the diverse functions of cell-to-cell events, both in normal physiology and in disease, is important for the development of more effective cancer therapies.

The review delves into the emergence, genetic underpinnings, and evolutionary history of cell-to-cell phenomena, shedding light on behavior once thought to be an anomaly. The researchers reviewed more than 500 articles to catalog the different forms of cell-to-cell phenomena observed in the tree of life.

The study described 16 different taxonomic groups in which cell-to-cell behavior was found to occur. Cell-to-cell events were classified into six distinct categories based on the degree of connectivity between the host and prey cells, as well as the outcome of the interaction (whether one or both cells survived).

The research highlights a range of cell-to-cell behaviors, ranging from completely selfish acts in which one cell kills and engulfs another, to more cooperative interactions in which both cells stay alive. For example, the researchers found evidence of “heterospecific killing,” in which a cell engulfs and kills a cell of a different species, in a wide range of unicellular, facultatively multicellular, and obligate multicellular organisms. In contrast, “conspecific killing,” in which one cell consumes another cell of the same species, is less common, observed in only three of the seven major taxonomic groups examined.

Obligate multicellular organisms are those that must exist in multicellular form throughout their life cycle. They cannot survive or function as single cells. Examples include most animals and plants. Facultative multicellular organisms are organisms that can exist either as single cells or in multicellular form depending on environmental conditions. For example, some types of algae can live as single cells under some conditions but form multicellular colonies under others.

The team also documented cases of cell-to-cell phenomena in which both host and prey cells remain alive after the interaction, suggesting that these events may serve important biological functions beyond simply killing competitors.

“Our categorization of cell-in-cell phenomena in the tree of life is important for a better understanding of the evolution and mechanism of these phenomena,” says Kapsetaki. “Why and how exactly do they happen? This is a question that requires further study in millions of living organisms, including organisms where cell-to-cell phenomena may not yet have been sought.”

Ancient genes

In addition to cataloging the diverse cell-to-cell behaviors, researchers are also investigating the evolutionary origins of the genes involved in these processes. Surprisingly, they found that many of the key cell-to-cell genes appeared long before the evolution of obligate multicellularity.

“When we look at genes associated with known cell-to-cell mechanisms in species that diverged from the human lineage long ago, it turns out that human orthologs (genes that evolved from a common ancestral gene) are usually associated with normal functions of multicellularity, such as immune surveillance,” says Cisneros.

A total of 38 genes related to the cell-in-cell phenomenon were identified, and 14 of them arose more than 2.2 billion years ago, predating the common ancestor of some facultatively multicellular organisms. This suggests that the molecular machinery for cell cannibalism evolved before the major transitions to complex multicellularity.

The ancient cell-to-cell genes identified in the study are involved in a variety of cellular processes, including cell-cell adhesion, phagocytosis (swallowing), intracellular killing of pathogens and regulation of energy metabolism. This diversity of functions indicates that cell-to-cell events likely played an important role even in unicellular and simple multicellular organisms long before the emergence of complex multicellular life.