Senescent Cells Fuel Lung Tumors

Macrophages are white blood cells that act as the body's first line of infection defence. In addition to killing hazardous pathogens, macrophages can initiate an immune response against cancers. However, like other cells, macrophages can experience senescence, which is connected with ageing, disease, and a number of physiological difficulties.

Senescent cells stop dividing, however, they do not die and are not usually eliminated from the body. They can stay and build in tissues, and they may secrete toxic chemicals. This is why senescent cells are referred to as "zombie cells." The reason why healthy cells become senescent is unknown.

Researchers detected senescent macrophages in the lung that not only remained but also supported tumour growth in a recent Cancer Cell study.

"Conceptually, the idea that a macrophage can become senescent and be tumour-promoting is unexpected," said Darren Baker, PhD, a Mayo Clinic senescent cell biologist and senior author of the study. "This finding brings us one step closer to better understanding how tumours and cancer form at the cellular level."

Dr. Baker and his colleagues found that senescent macrophages appear to block the immune system from being able to respond to and eliminate the abnormal growth of cells. This leads to a tumour.

"Through different experiments and analyses, we could distinguish those senescent macrophages from the other macrophages. We found that if we eliminate them, through genetic or pharmacological approaches, we delay tumour formation," said lead author Luis Prieto, PhD, a postdoctoral fellow and recent graduate of the Mayo Clinic Graduate School of Biomedical Sciences.

The researchers reasoned that precancerous cells communicated with the surrounding cells, including macrophages, and triggered the macrophages to become senescent. In turn, the senescent cells then appeared to alter the surrounding area in a way that promoted tumour growth.

Initially, the researchers thought removing the senescent cells would result in more adenomas, the type of lung tumour studied. However, the results of their early experiments showed otherwise

"It was very challenging, because every time we would do an experiment, it was just the opposite of what we'd expect," Dr Prieto said. "If one removes tumour suppressors regulating senescent cells, one would expect to have more tumours, but it actually just happened to have the opposite results. There were fewer tumours in the absence of those tumour suppressors."

The researchers worked with study co-author Hu Li, PhD, an individualized medicine researcher at Mayo Clinic, and conducted single-cell RNA sequencing in his lab. This work helped them identify lung macrophages as a key cell type driving tumour growth. Now, they believe the macrophages are responding to the precancerous cells as they begin to cause tumours.

"We had to rethink our initial ideas as we learned a lot more about what cells can do. Then, it started to make a lot more sense about how senescent macrophage cells can influence other cells, the environment and the immune system in this case," Dr. Baker said.