Cancer Cell Cannibalistic Mechanisms Uncovered

A cell in the process of dividing (center) that is being engulfed by cells on either side. DNA is shown in blue and a protein responsible for attachment between cells is shown in green. [Dr. Jo Durgan/Babraham Institute]

It should come as no surprise that cancer cells undergo some unusual behavior throughout their lifespan. However, cannibalism—scientifically referred to as entosis and something that has been observed in tumor cells for over a century—still tops the list as one of their weirder traits. Now a team of investigators from the Babraham Institute, Memorial Sloan Kettering Cancer Center, and the Francis Crick Institute has just revealed some new data about this understudied area that may offer some surprising insights into cancer biology. Findings from the new study were published recently in eLife in an article entitled “Mitosis Can Drive Cell Cannibalism through Entosis.”       

“We set out to identify the proteins that control cell cannibalism in tumor cells, but by using time-lapse microscopy to watch this process in action, we stumbled across a completely unexpected new mechanism,” explained lead study investigator Joanne Durgan, Ph.D., a senior postdoctoral fellow at the Babraham Institute. “The link we've found to cell division is really intriguing from the perspective of cancer.”

Entosis primarily occurs when one cell surrounds, kills, and digests another. Entosis doesn't typically happen between healthy cells, but it is common in tumors. In this new study, the researchers found that cannibalism can be triggered by mitosis. Moreover, since uncontrolled cell division is a hallmark of cancer, these new findings suggest that cannibalism may play a vital role in resisting cancer.

The study investigators focused their research efforts on human epithelial cells, as these cells form many of the surfaces in the body and give rise to over 80% of human cancers. Typically, epithelial cells remain firmly attached to their surroundings when they divide. However, data from the current study shows that weakened attachments result in more cell cannibalism. This may explain why drugs that weaken cell attachments are effective anticancer drugs.

A new mechanism of cell cannibalism by entosis. A cell divides and one of the new cells is swiftly cannibalized by a nearby cell. [Dr. Jo Durgan/Babraham Institute].

(Left) A dividing cell (lower right) in the process of being engulfed by another cell (center). (Right) A dividing cell that has been completely consumed by another cell. DNA shown in blue. A protein involved in contact between cells shown in green. [Dr. Jo Durgan/Babraham Institute]

“We report an alternative mechanism for entosis in human epithelial cells, driven by mitosis,” the authors wrote. “Mitotic entosis is regulated by Cdc42, which controls mitotic morphology. Cdc42 depletion enhances mitotic deadhesion and rounding, and these biophysical changes, which depend on RhoA activation and are phenocopied by Rap1 inhibition, permit subsequent entosis. Mitotic entosis occurs constitutively in some human cancer cell lines and mitotic index correlates with cell cannibalism in primary human breast tumours. Adherent, wild-type cells can act efficiently as entotic hosts, suggesting that normal epithelia may engulf and kill aberrantly dividing neighbours.”

Cell cannibalism has a complex relationship with cancer, and it is not completely clear whether it helps or hinders tumor growth. Still, the discovery that dividing cells are more likely to be cannibalized by other cells suggests that entosis may help to slow or prevent cancer by causing cancer cells to be consumed and destroyed by nearby healthy cells.

“Entosis is a fascinating process that may play a role in normal physiology, as well as cancer, remarked senior study investigator Oliver Florey, Ph.D., a group leader at the Babraham Institute. “By studying entosis, we hope to gain insights into fundamental cell biology, as well as to explore intriguing new avenues for cancer research. After 100 years of observing cell-in-cell structures, there is now an exciting push toward discoveries in both cell and cancer biology.”

The investigators were excited by their findings and are optimistic about future steps toward elucidating the entire entotic molecular signaling pathway. “Our data uncover an intriguing link between cell division and cannibalism, of significance to both cancer and chemotherapy,” the authors concluded.