Researchers find mechanisms behind malignant lung tumor progression

Mutations affecting the MAP kinase and PI3’-kinase pathways—both important for controlling cellular growth—may coordinate to promote malignancy in lung tumors and must act together to do so, according to the results from a study published in eLife.

Roughly three-quarters of all individuals with lung adenocarcinomas—the most common form of lung cancer—have MAP kinase pathway and PI3’-kinase pathway mutations. Both of these pathways play a role in cell growth and proliferation.

"We knew that mutations in the MAP kinase pathway promote the growth of benign lung tumors, but that PI3'-kinase mutations alone do not kickstart tumor formation in the same cells," explained lead author J. Edward van Veen, PhD, former postdoctoral fellow in senior author Martin McMahon's laboratory, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT. "The pathways instead cooperate to drive the growth of malignant tumors, but we didn't know what molecular changes occurred as a result of this cooperation and how the lung cells lose their characteristics as cancer develops."

To this end, Dr. van Veen and colleagues used genetically engineered mice with mutations specific to type II pneumocytes (the MAP kinase and the PI3’-kinase mutations) to assess the effects of these mutations on lung cells at various stages of tumor development.

When present alone, only the MAP kinase mutation—not the PI3’-kinase mutation—could change type II lung cells into small, benign tumors, they found. When both mutations were present, however, lung cancer tumors became more aggressive because cells stopped producing proteins normally made by type II cells (pneumocytes).

Further, in tumors driven by MAP and PI3’-kinase, they found reduced numbers of the genes that typify type II pneumocytes, which suggested that these cells had dedifferentiated, or lost their specialized function and reverted to an earlier developmental state. Dedifferentiation is frequently and opportunistically used by cancer cells to overthrow cellular machinery, subverting it to its own purposes (ie, survival and proliferation).

Digging deeper, Dr. van Veen and colleagues used fluorescent labeling of lung cell specialization molecules. These molecules, they found, had no role in dedifferentiation. Instead, what they found implicated peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) as the culprit in cellular dedifferentiation. Again, going deeper, the team studied mice with silenced PGC-1α, in tandem with MAP kinase pathway mutations, and found that silencing PGC-1α caused dedifferentiation of lung cells.

"Taken together, our results shed light on the mechanisms by which pathways involved in lung tumor development also cooperate to influence the specialization of tumor cells," said senior author Martin McMahon, PhD, senior director, Preclinical Translation, Huntsman Cancer Institute, and professor, Department of Dermatology, University of Utah. "Since both MAP kinase and the PI3'-kinase pathways are targets for drug development, this study may influence the deployment of drugs currently in clinical trials, the interpretation of trial results and the process of novel lung cancer drug discovery."