New research has revealed the chameleonic abilities of lung cancer cells: by adopting the traits of cells from other major organs, lung cancer cells may escape chemotherapy. The findings open up paths for more targeted therapies.
The disease also has one of the lowest survival rates — partly because lung cancer tumors are either treatment-resistant from the start or they develop resistance to treatment over time.
What is more, the new study — which was led by Purushothama Rao Tata, an assistant professor of cell biology at Duke University School of Medicine in Durham, NC, and published in the journal Developmental Cell — finds a genetic mutation and mechanism that drive this shape-shifting process.
Prof. Tata and his team analyzed genetic data from a large genetic database, which amassed thousands of samples from 33 different types of cancer, and profiled their genomes.
The researchers focused on the so-called non-small cell lung cancer, which makes up 80–85 percent of all lung cancer cases.
On analyzing the genomes of lung cancer tumors, the scientists found that a large number of them lacked NKX2-1. This is a gene known for “telling” cells to develop specifically into a lung cell.
Instead, the team found that these cells had genetic traits normally linked with gastrointestinal organs — such as the pancreas, duodenum, and small intestine — and the esophagus and liver.
Based on these preliminary observations, the scientists hypothesized that knocking out the NKX2-1 gene would make lung cancer cells lose their identity and adopt that of neighboring organs.
So, the researchers tested this hypothesis in two different mouse models. In the first, they depleted the rodents’ lung tissue of the NKX2-1 gene. Doing so made the lung tissue change its appearance and, surprisingly, its behavior.
A microscopic analysis of the lung tissue revealed that it had started to resemble gastric tissue in its structure, as well as produce digestive enzymes.
Next, Prof. Tata and team wondered what would happen if they activated two oncogenes: SOX2 and KRAS. Triggering the former led to tumors that looked as though they resided in the foregut, while activating the latter caused tumors that looked as if they were in the mid- and hindgut.
Together, the authors conclude, “These findings demonstrate that elements of pathologic tumor plasticity mirror the normal developmental history of organs in that cancer cells acquire cell fates associated with developmentally related neighboring organs.”
Prof. Tata, who is also a member of the Duke Cancer Institute, explains what the findings mean for understanding how lung cancer might develop chemotherapy resistance.
“Cancer cells will do whatever it takes to survive,” he explains. “Upon treatment with chemotherapy, lung cells shut down some of the key cell regulators and pick up the characteristics of other cells in order to gain resistance.”
“Cancer biologists have long suspected that cancer cells could shape-shift in order to evade chemotherapy and acquire resistance, but they didn’t know the mechanisms behind such plasticity.”
Prof. Purushothama Rao Tata
“Now that we know what we are dealing with in these tumors,” he adds, “we can think ahead to the possible paths these cells might take and design therapies to block them.”