In addition to competing for resources, living cells actively kill and eat each other. New explorations of these “cell in cell” phenomena show that they are not limited to cancer cells but constitute a common facet of living organisms, throughout the tree of life. Credit: Jason Drees for the Biodesign Institute at Arizona State University
New research reveals that cell-in-cell phenomena, in which one cell consumes another, are common to all life forms and important for normal biological functions, and are not only associated with cancer.
In a recent review article, Carlo Maley and his team at Arizona State University explore the cell-in-cell phenomenon where one cell engulfs and sometimes consumes another. The study shows that instances of this behavior, including cellular cannibalism, are widespread across the tree of life.
The results challenge the common perception that cell-in-cell events are largely limited to cancer cells. Rather, these events appear to be common to diverse organisms, from single-celled amoeba 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 propose 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 as an approach to cancer treatment should be abandoned, as these phenomena are not unique to malignancy.
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 reconsider fundamental concepts of cellular cooperation, competition and the complex nature of multicellularity. The study opens new avenues of research in evolutionary biology, oncology and regenerative medicine.
The new research, published in the journal Nature 
Carlo Maley is a researcher at the Biodesign Center for Biocomputing, Security and Society; professor in the ASU School of Life Sciences; and director of the Arizona Cancer Evolution Center. Credit: The Biodesign Institute at Arizona State University
“We started this work because we learned that cells don’t just compete for resources, they actively kill and eat each other,” Maley says. “It’s a fascinating aspect of cancer cell ecology. But further exploration revealed that these phenomena occur in normal cells and sometimes neither cell dies, giving rise to an entirely new type of hybrid cell.
Maley is a researcher at the Biodesign Center for Biocomputing, Security and Society; professor in the ASU School of Life Sciences; and director of the Arizona Cancer Evolution Center.
The study was conducted in collaboration with first author Stefania E. Kapsetaki, formerly at ASU and now a researcher at Tufts University, and Luis Cisneros, formerly at ASU and currently a researcher at the Mayo Clinic.
From selfish to cooperative cellular interactions
Cell-in-cell events have been observed for a long time but remain poorly understood, particularly outside the context of immune responses or cancer. The first genes responsible for cell-in-cell behavior date back more than 2 billion years, suggesting that these phenomena play an important, although still undetermined, role in living organisms. Understanding the diverse functions of cell-in-cell events, both in normal physiology and in disease, is important for developing more effective anticancer therapies.
The journal examines the appearance, genetic underpinnings and evolutionary history of cell-in-cell phenomena, shedding light on behavior 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. Cell-in-cell events were classified into six distinct categories based on the degree of relationship between host and prey cells, as well as the outcome of the interaction (whether one or both cells survived).
The study highlights a broad spectrum of cell-to-cell behaviors, ranging from completely selfish acts, in which one cell kills and consumes another, to more cooperative interactions, in which both cells remain alive. For example, researchers have found evidence of “heterospecific killing,” in which one cell engulfs and kills a cell of a different type.
” data-gt-translate-attributes=”({“attribute”:”data-cmtooltip”, “format”:”html”})” tabindex=”0″ role=”link”>species, in a wide range of unicellular, facultative multicellular and obligate multicellular organisms. In contrast, “conspecific killing,” in which one cell consumes another cell of the same species, was less common, observed in only 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 single cells. Examples include most animals and plants. Facultative multicellular organisms are organisms that can exist as single cells or in multicellular form depending on environmental conditions. For example, certain types of algae can live as single cells under certain conditions but form multicellular colonies in others.
The team also documented cases of cell-in-cell phenomena in which host and prey cells remained alive after the interaction, suggesting that these events could 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,” explains Kapsetaki. “Why and how exactly does this happen? This is a question that requires further research on millions of living organisms, including organisms for which cell-in-cell phenomena may not yet have been investigated.
Ancient genes
In addition to cataloging the various cell-in-cell behaviors, the researchers also studied the evolutionary origins of the genes involved in these processes. Surprisingly, they found that many of the key cell-in-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 a long time ago, it turns out that human orthologs (genes that evolved from a gene common ancestral) are generally associated with normal functions of multicellularity, such as immune surveillance,” explains Cisneros.
In total, 38 genes associated with cell-in-cell phenomena have been identified, and 14 of them appeared more than 2.2 billion years ago, predating the common ancestor of certain facultative multicellular organisms. This suggests that the molecular machinery responsible for cellular cannibalism evolved before major transitions to complex multicellularity.
The ancient cell-in-cell genes identified in the study are involved in various cellular processes, including cell-cell adhesion, phagocytosis (engulfment), intracellular killing of pathogens, and regulation of energy metabolism. This diversity of functions indicates that cell-in-cell events likely played an important role even in simple unicellular and multicellular organisms, long before the emergence of complex multicellular life.
Reference: “Cell-in-cell phenomena across the tree of life” by Stefania E. Kapsetaki, Luis H. Cisneros and Carlo C. Maley, March 29, 2024, Scientific reports.
DOI: 10.1038/s41598-024-57528-7