Cannibalism at the cellular level is common across most life forms

Researchers have uncovered the fascinating and widespread phenomenon of cell-in-cell events, where one cell engulfs and sometimes consumes another in a type of cellular cannibalism.

This study, led by scientists from Arizona State University, challenges the long-held belief that such behavior is unique to cancer cells. Instead, these interactions are common across diverse life forms, from single-celled organisms to complex multicellular animals.

Widespread occurrence of cellular cannibalism

The research reveals that cell-in-cell events are not restricted to cancerous behavior. These interactions are prevalent in non-cancer cells, suggesting that they play vital roles in normal development, homeostasis, and stress response.

The researchers argue that targeting cell-in-cell events as a cancer treatment strategy should be reconsidered, as these behaviors are deeply embedded in the genetic makeup of a wide array of organisms.

Challenging conventional views on cellular behavior

Published in the renowned scientific journal Scientific Reports, the study is the first to systematically investigate cell-in-cell phenomena across the tree of life.

By demonstrating that these occurrences span numerous life forms, the research encourages a reevaluation of fundamental concepts of cellular cooperation, competition, and the complexity of multicellularity. This discovery opens new avenues for research in evolutionary biology, oncology, and regenerative medicine.

“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 Carlo Maley of ASU.

“That’s a fascinating aspect of the ecology of cancer cells. But further exploration revealed that these phenomena happen in normal cells, and sometimes neither cell dies, resulting in an entirely new type of hybrid cell,” he continued.

Evolutionary significance of cell-in-cell events

The earliest genes responsible for cell-in-cell behavior date back over 2 billion years, indicating that these phenomena play an important, though not yet fully understood, role in living organisms.

Understanding the diverse functions of cell-in-cell events in both normal physiology and disease is crucial for developing more effective cancer therapies.

Cataloging the diversity of cellular cannibalism

The review delves into the occurrence, genetic underpinnings, and evolutionary history of cell-in-cell phenomena. The researchers reviewed more than 500 articles to catalog various forms of these interactions across the tree of life.

They identified 16 different taxonomic groups where cell-in-cell behavior occurs and classified these events into six distinct categories based on the relationship between the host and prey cells and the outcome of the interaction.

A spectrum of cell-in-cell behaviors is highlighted in the study, ranging from selfish acts, where one cell kills and consumes another, to cooperative interactions, where both cells remain alive.

For instance, “heterospecific killing,” where a cell engulfs and kills a cell of a different species, was observed across a wide range of organisms. In contrast, “conspecific killing,” where a cell consumes another cell of the same species, was less common.

Important biological functions beyond competition

The team also documented cases where both the host and prey cells remained alive after the interaction, suggesting that these events may serve significant biological functions beyond just killing competitors.

“Our categorization of cell-in-cell phenomena across the tree of life is important for better understanding the evolution and mechanism of these phenomena,” says first author Stefania E. Kapsetaki.

“Why and how exactly do they happen? This is a question that requires further investigation across millions of living organisms, including organisms where cell-in-cell phenomena may not yet have been searched for,” she continued.

Evolutionary origins of cellular cannibalism

The researchers investigated the evolutionary origins of the genes involved in cell-in-cell processes. They found that many key genes emerged 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 a very long time ago, it turns out that the human orthologs are typically associated with normal functions of multicellularity, like immune surveillance,” explains  Luis Cisneros, formerly with ASU and currently a researcher at Mayo Clinic.

In total, 38 genes associated with cell-in-cell phenomena were identified, with 14 of these originating over 2.2 billion years ago, predating the common ancestor of some 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 are involved in various cellular processes, including cell–cell adhesion, phagocytosis, intracellular killing of pathogens, and regulation of energy metabolism.

This diversity of functions indicates that cell-in-cell events likely played important roles even in single-celled and simple multicellular organisms well before the emergence of complex multicellular life.

Cellular cannibalism and the future of medicine

In summary, this study revolutionizes our understanding of cell-in-cell phenomena, cellular cannibalism, revealing their widespread occurrence across the tree of life and challenging the notion that these events are unique to cancer cells.

By demonstrating the ancient evolutionary origins of cell-in-cell genes and the diverse roles these interactions may play in normal development, homeostasis, and stress response, the research highlights new areas for investigation in evolutionary biology, oncology, and regenerative medicine.

As we continue to unravel the complexities of cellular behavior and its implications for the evolution of multicellularity, this study serves as a catalyst for further exploration, inviting us to reconsider fundamental concepts of cellular cooperation, competition, and the intricate dance of life at the cellular level.

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

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

The full study was published in the journal Scientific Reports.

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