super competitor cells (green) cheat to take over_a developing fly wing_3x.png

Some Cells Win, Some Lose, But Still Others Cheat

October 11, 2018

From worms to humans, individual cells in multicellular organisms are frequently ordered to die for the greater good. Whether the cell is infected by a pathogen or harbors a dangerous mutation, organisms have developed sophisticated systems of cell suicide and homicide to eliminate threatening cells.

How do organisms decide which cells must be eliminated? Oftentimes, the decision comes down to a fitness competition among cells. These contests, occurring within a neighborhood of cells, measure each cell’s quality, deems some cells as “winners,” and eliminates less-fit “loser” cells.

But some cells can cheat their way into looking like winners, allowing them to thrive at the expense of their neighbors, according to a new study led by Laura Johnston, PhD, professor of genetics & development at Columbia University Vagelos College of Physicians and Surgeons.

Learning more about how cells cheat could give researchers a better understanding of how nascent cancer cells covertly take over healthy tissues.

 

How cells compete

The first systems governing cell competition were discovered by studying wing development in the fruit fly Drosophila. It’s easy to manipulate wing development in the lab, and researchers can easily track the effects of their manipulations in minute detail.

To learn more about how Drosophila cells compete, Johnston created “super-competitor” cells—which always win—by activating a gene called Myc. Myc is widely known as a cancer-causing oncogene in humans. Although cells with a mutated Myc gene lose to normal cells in competition, cells with extra Myc activity do the opposite and defeat normal cells.

Using Myc super-competitor cells, the Johnston lab had previously identified many of the proteins used during competition to eliminate loser cells in developing fly wings.

The new study, done primarily by a PhD student, Lale Alpar, provides critical new insights, including where the proteins come from, how they’re activated, and how cells sense their level of fitness relative to their neighbors.

Super-competitor cells_(green)_cheat to take_over_developing_wing_tissue_(blue)
Super-competitor cells (green) cheat in cell competition and take over tissue (blue) in a developing wing of a fruit fly. A similar process may occur in cancer. Image: Laura Johnston / Columbia University Irving Medical Center.

 

Some cells cheat to win

But they also learned that the so-called “super-competitor” cells win because they’re cheating.

In the type of cell competition Johnston studied, cells survey the fitness of their neighbors by releasing proteins that instruct other cells to commit suicide. All cells have receptors that pick up these signals, which can be ignored by robust cells, while less-fit cells succumb to the instructions.

diagram that illustrates how super competitor cells tell neighboring normal cells to die
Super-competitor cells "cheat" in cell competitions by sending out large quantities of death signals (grey circles) that tell neighboring normal cells to commit suicide, while protecting themselves from the signals by reducing the number of receptors (circled red) that intercept the signals.

Myc super-competitor cells cheat by secreting extra amounts of the suicide signal, which could potentially endanger the Myc cells themselves. But at the same time, the Myc cells make fewer receptors, making themselves deaf to the suicide signal. Nearby normal cells are overwhelmed by the suicide signal and die, allowing the Myc cells to expand their territory in the tissue.

"Myc cells are perfect cheaters; they can basically make the components to activate suicide signaling while at the same time rebuff the signaling," says Johnston.

Cheating cells and cancer

Cell competition is thought to occur regularly in tumors, and similar mechanisms may help drive it.

"Cancer is basically a disease of cells with different fitness," says Johnston. Very early, pre-malignant tumor cells would benefit from eliminating normal neighbors, she adds, which could help them take over more tissue.

Tests to detect that process, she says, might reveal tumors long before they get out of control.

 

 

References

More information

The paper, “Spatially Restricted Regulation of Spätzle/Toll Signaling during Cell Competition,” was published Sept. 24 in Developmental Cell.

Cora Bergantiños, PhD, also contributed to the work (Columbia University Irving Medical Center).

The authors declare no competing interests.

The research was supported by the NIH (grants RO1GM078464 and R01CA192838) and the Leukemia & Lymphoma Society.