Even when patients are treated with targeted cancer therapies, many lung cancer patients suffer a recurrence. Researchers at Cold Spring Harbor Laboratory wanted to uncover how some cancers escape the power of targeted treatment. Their work was published in the journal eLife this week.
The team of scientists, lead by Raffaella Sordella, found that a tiny subset of cells in or around a cancerous tumor can change over time and become the seeds of a killer relapse.
“It’s well known that individual tumors are heterogeneous. They’re made up of cells that look and behave very differently from one another,” Sordella said. “These basic differences among cells within a single tumor can be caused by non-genetic mechanisms, including cell-to-cell signaling, which can include the release of cytokines, small proteins that engage cells of the patient’s immune system and alter tumor dynamics.”
“Genetic mutations can occur as the tumor is evolving over time. Sometimes these mutations cause changes in the activity of other genes, further destabilizing the cell,” she added.
Sordella said her team’s results “provide evidence that phenotypic diversity – non-genetic changes of a tumor cell’s shape, surface markings, behavior – can actually be the cause of genetic diversity in the tumor, helping it to survive, thrive, and eventually kill the patient.”
They discovered that in tissue samples from patients with lung cancer, the signaling molecule TGF-β is activated in particular cells generated via a non-genetic mechanism. In these cells, TGF-β decreases the expression of genes involved in DNA repair. Because these cells don’t repair damage as frequently as their counterparts, they disproportionately accumulate gene copy number alterations and the total population of these tumor cells becomes more diverse.
“It was great not only to be able to describe these findings in the context of traditional in vitro cancer cell line models, but also in real patients. This was possible thanks to our collaboration with the thoracic surgery departments of Huntington Hospital and LIJ, spurred and supported by the new alliance between CSHL and the Northwell Health system,” Sordella said.
In other biological systems, increased genetic diversity can lead to populations of bacteria or viruses better adapting to changing conditions. Sordella’s team showed that the increase in genetic diversity among cancer cells with damaged DNA-repair mechanisms could be a contributing factor to resistance from cancer-killing drugs.
“A corollary to this discovery is that killing cancer cells that are more genetically unstable in the earlier stages of tumorigenesis could result in improved outcomes in currently used cancer treatments,” she explained.
