Lung tumors have been found to morph into developmentally related neighboring organs, namely the gut.TATA LAB/DUKE UNIVERSITY
Embedded in a lung cancer tumor, scientists have found a gastrointestinal tract in miniature.
Duke University researchers have observed rudimentary, but functional, stomachs, small intestines, and duodenums growing inside cancerous lungs — illustrating how varied and plastic these metastatic cells can be.
Cancerous cells, after all, use the very same developmental mechanisms as healthy cells do to adapt and survive. So scientists are observing an example of some cells mutating into their developmental cousins.
“During development, the lung and the esophagus all come from the same endodermal progenitor cells,” said Purushothama Rao Tata, lead author of a study about the research and an assistant professor of cell biology at Duke University. “What we think is that these cancer cells in the lung slide into the nearest developmental neighborhood.”
Tata’s group found that a large proportion of human lung cancer cells lack a developmental gene called NKX2-1, which helps stem cells morph into lung cells. So these cancer cells defaulted to another developmental pathway — instead of taking advantage of the coding that turns stem cells into gut. Indeed, Tata found that many lung cancer cells expressed genes associated with gastrointestinal organs.
“We’ve been most interested in how cells maintain their identity, and what goes wrong in tumor cells so they change their behavior,” Tata said.
This mechanism likely contributes to drug resistance, Tata said. Cancer cells, after all, will do just about anything to survive — and in this instance, lung cells will pick up the characteristics of gut cells to help evade treatment.
Tata was able to reproduce his findings in animal models: When he knocked out the NKX2-1 gene in the lung tissue of mice, he found that tissues that typically only appear in the gut began growing in their lungs. These structures actually excreted digestive enzymes.
The work, while interesting, is “not entirely surprising,” said Deborah Caswell, a researcher at the Francis Crick Institute who studies tumor heterogeneity, particularly in lung cancer. What she finds particularly intriguing, however, is that distinct regions within a single tumor can differentiate in unique ways.
“This finding should improve our ability to model and predict how individual tumor cells will evolve as tumors progress,” Caswell said. It helps illustrate how tumor plasticity and heterogeneity work, she said — and could help scientists develop better therapies to combat drug resistance.
Tata’s group now plans to test new drug combinations in miniaturized tumor models.
“We haven’t tested it yet, but based on our findings here, we’re hypothesizing that colon cancer drugs might help treat some lung cancers,” Tata said.