Lung Cancer Cells Rely on Symbiotic Relationship to Metastasize

Leader and follower cells depend on each other for survival and invasion.

A symbiotic relationship among lung cancer cells allows them to survive and metastasize, according to a study published in Nature Communications.

When cancer cells split from tumors, they are thought to travel as a pack—referred to as collective invasion. The members of the invasive pack are not all alike and have specialized roles as leaders and followers.

Both the leaders and followers rely on each other for mobility and survival. The differences between these cells specialized roles and their interdependence could be keys to the development of treatments that impair or prevent cancer metastasis.

“We’re finding that leader and follower cells have a symbiotic relationship and depend on each for survival and invasion,” said senior author Adam Marcus, PhD. “Because metastatic invasion is the deadliest aspect of cancer, our goal is to find agents that disrupt that symbiotic relationship.”

For the study, the investigators examined how a mass of lung cancer cells behaved when embedded in a 3-D protein gel. In general, the cells stuck together, but occasionally there were a few cells that would extend outside of the mass, like tentacles, with the leader cell at the tip.

“We saw that when the leader cell became detached or died unexpectedly, the follower could no longer move,” said Jessica Konen, PhD. “In one particular movie, we saw a leader cell come out away from the rest of the cells, and then seemed to realize that nobody was following him. He actually did a 180, and went back to grab cells to bring with him.”

To examine what differentiated leader cells from follower cells, the investigators developed a technique, called SaGA, for spatiotemporal genomic and cellular analysis. The technique marked the culture cells with a laser to change them from a fluorescent green to red, and then isolating the red cells.

The investigators found that the isolated leader cells maintained their invasive behavior and had a distinctive shape. Once the isolated cells were added back to the purified followers, the leader cells restored the followers’ mobility and invasive behavior. This occurred even if the leaders comprise only 1% of the mix.

Although the leader cell state is durable, the followers will spawn new leaders after a month or 2 of growth in culture, according to the researchers.

There are several key differences between leader and follower cells, including that leader cells secrete more vascular endothelial growth factor (VEGF) than followers do.

Leader cells do not require VEGF to engage in invasive behavior, but it is important for pack formation. This is because it is a mobility factor that leaders provide the followers with. In return, followers provide leaders with the ability to grow and survive.

When leaders and followers grow separately, the leaders increase their numbers at a much slower rate and have erratic cell cycles, as well as more bulges in the cell membrane.

Other molecular differences between leaders and followers is traction-generating focal adhesion kinase (FAK) activity in leader cells and growth-promoting Notch signaling in followers. Both of which are potential avenues for disrupting the symbiotic relationship, according to the authors.

Although the study focused on lung cancer cells, a similar phenomenon of collective invasion is observed in breast cancer. However, different genes and biological pathways appear to be important in each system.

“I think what’s need for collective invasion will depend on the environmental stresses the cancer cells face, and it may shift with treatment,” Marcus concluded.