Study finds widespread “cell cannibalism” and related phenomena across the tree of life

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

The results challenge the widely held belief that cell-in-cell events are largely limited 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” behavior. Rather, the researchers suggest that cell-in-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-in-cell events should be abandoned as an approach to cancer treatment because these phenomena are not unique to malignancies.

By showing that occurrences occur in a variety of life forms and are deeply rooted in our genome, the research invites us to rethink fundamental 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 reportsis the first team to systematically study cell-in-cell phenomena across the tree of life. The group’s findings could help redefine the understanding of cell behavior and its implications for multicellularity, cancer, and the evolution of life itself.

“We did this work for the first time 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 cancer cell ecology. But further research revealed that these phenomena occur in normal cells and sometimes no cell dies, leading to an entirely new type of hybrid cell.”

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

The study was conducted in collaboration with lead 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 cell interactions

Cell-in-cell events have long been observed but remain poorly understood, particularly outside the context of immune responses or cancer. The earliest genes responsible for cell-in-cell behavior date back more than two billion years, suggesting that these phenomena play an important – if still unclear – role in living organisms. To develop more effective cancer therapies, it is important to understand the diverse functions of cell-in-cell events in both normal physiology and disease.

The paper addresses the occurrence, genetic basis and evolutionary history of cell-in-cell phenomena and sheds light on behavior that was once considered an anomaly. The researchers reviewed more than 500 articles to catalog the various forms of cell-in-cell phenomena observed across the tree of life.

The study describes 16 different taxonomic groups in which cell-in-cell behavior occurs. The cell-in-cell events were divided into six different categories based on the degree of relatedness between the host and prey cells as well as the outcome of the interaction (whether one or both cells survived).

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

Obligate multicellular organisms are those that must exist in a multicellular form throughout their life cycle. They cannot survive or function as individual cells. Examples of this 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, certain species of algae can live as single cells under certain conditions, but form multicellular colonies under others.

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

“Our categorization of cell-in-cell phenomena across the tree of life is important to better understand the evolution and mechanism of these phenomena,” says Kapsetaki. “Why and how exactly do they occur? This question requires further study of millions of living organisms, including organisms in which cell-in-cell phenomena may not yet have been investigated.”

Old genes

In addition to cataloging the diverse cell-to-cell behaviors, the researchers also investigated the evolutionary origins of the genes involved in these processes. Surprisingly, they found that many of the most important cell-to-cell genes arose long before the evolution of obligate multicellularity.

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

A total of 38 genes associated with cell-in-cell phenomena have been identified, and 14 of these arose over 2.2 billion years ago, predating the common ancestor of some facultative multicellular organisms. This suggests that the molecular machinery for cell cannibalism evolved before the major transitions to complex multicellularity.

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