Photo Credit: iStock.com/Jose Luis Calvo Martin & Jose Enrique Garcia-Maurino Muzquiz

A recent study reports that disruption of tracheal basal cell homeostasis is the key cellular event driving lung squamous cell carcinoma development.

Disruption of basal cell homeostasis in the trachea has been identified as the pivotal cellular event in the development of lung squamous cell carcinoma, according to findings published online in Science.

“We found that a subset of cells expressing the gene Krt5 becomes dominant and starts pushing out normal cells. This expansion becomes dramatic, and eventually the descendants of just a few cells that originated in the trachea invade and conquer normal cells, in some cases going on to populate whole lobes of the lung. It is these cells that eventually form tumors,” explained study senior author Sam Janes, MBBS, FRCP, MSc, PhD, University College London, in a press release.

Basal Cell Dynamics in Carcinogen-Exposed Airways

The discovery stemmed from research involving both mice and humans.

In mice, researchers labeled Krt5-expressing basal cells in the trachea to track the descendants of these cells over time. Basal cells and their descendants in mice without carcinogen exposure remained in their original location in the trachea, the researchers found. However, basal cells in mice exposed to a tobacco-smoke carcinogen gradually multiplied before breaching the tracheal boundary and spreading into the lungs.

“There is a natural balance between the different cell populations and types, but when these cell populations are exposed to carcinogens like those found in tobacco smoke, this balance is disrupted,” noted study first author Sandra Gómez-López, PhD, University College London. “Our experiments have shown that populations of cells originating from just a few damaged basal cells in the trachea gradually become dominant, taking over large areas of the lung.”

Emergence of Transitional Cell Population

The researchers also performed single-cell RNA sequencing of tracheal cells from healthy mice and mice exposed to carcinogens, as well as from humans who did not smoke and those who did smoke. Their findings showed that as damaged basal cells colonize the airways, a population of transitional cells expressing a different gene, Krt13, also becomes more abundant. Luminal cells, meanwhile, become scarce.

Moreover, DNA sequencing of the trachea and lung samples from people who had smoked revealed that cells from separate precancerous lesions descended from the same damaged basal cell, the research team reported.

Implications for Early Detection & Prevention

“By understanding the ‘cell of origin’ where these changes begin and how they develop, the ambition is that we will be able to design strategies to prevent lung cancer occurring in the first place,” said Dr Janes, “or at least detect it much earlier.”