Researchers Identify Genetic Mutations that Cooperate to Drive Cancer Development

Researchers have recently identified how two different gene mutations fuel the growth of cancers in the lung. This study utilized genetically engineered mice to analyze lung tumors as they progress from being small, invisible defects to larger, potentially fatal cancers. The results of this work, published on August 27 in the journal eLife, indicate new mechanisms of tumor development that will aid researchers in developing therapeutic agents that target lung cancer.

Lung cancer manifests in several forms, including non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths in the world. Roughly three-quarters of lung adenocarcinomas, the most common form of NSCLC, display mutations that impact two control mechanisms that are essential to cell growth. Specifically, these mutations manifest in the MAP kinase and the PI3’-kinase pathways. Mutations in either of these mechanisms on their own are not enough to cause lung cancer, but when these mutations occur in concert, cancer can grow.

“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 Ed van Veen, lead author, former Postdoctoral Fellow in senior author Martin McMahon’s laboratory at Huntsman Cancer Institute (HCI) at the University of Utah in Salt Lake City. “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.”

In their research, van Veen and colleagues studied mice with induced mutations in their Type 2 pneumocytes. Their goal in doing so was to analyze the effects these mutations have on the genes and proteins produced in these cells during different stages of cancer progression. The team found that these Type 2 pneumocytes showed decreased expression of genes unique to this cell type, indicating that these cells had lost their natural identity.

The team then examined which molecules took place in the coordination of MAP and PI3’-kinase pathways. Fluorescently labeling molecules that are already known to take part in the lung cell specialization showed that these molecules did not contribute to the loss of lung cell identity associated with cancer development. Instead, they identified the PGC1α protein as being responsible for this process.

van Veen and associates silenced the PGC1α gene and induced mutations in the MAP kinase pathway to investigate whether PGC1α controls this loss of cell identity directly during tumor progression. In doing so, they found that the lung cells did in fact lose their unique characteristics. This occurred in the cells through coordination with two other molecules responsible for this specialization.

“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 Martin McMahon, senior author, Senior Director of Preclinical Translation at HCI and Professor of Dermatology at the 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.”