MIT Scientists Use New Technique to Identify Lung Cancer Gene

Using whole-genome profiling, MIT scientist were able to pinpoint what appears to be a gene that drives progression of Small Cell Lung Cancer (SCLC).

The gene, which the researchers found overexpressed in both mouse and human lung tumors, could lead to new drug targets, says Alison Dooley, a recent PhD recipient in the lab of Tyler Jacks, director of MIT’s David H. Koch Institute for Integrative Cancer Research. Dooley is the lead author of a study describing the finding in the July 15 issue of Genes and Development.

Dooley and her colleagues studied the disease’s progression using a strain of mice, developed in the laboratory of Anton Berns at the Netherlands Cancer Institute, that deletes two key tumor-suppressor genes, trp53 and Rb1. The researchers were able to identify several frequent, high-magnitude focal DNA copy number alterations in the Small Cell Lung Cancer (SCLC). Uncovered amplification of a novel, oncognetic transcription factor, Nuclear factor I/B (NFIB), in the mouse(SCLC) model and in human (SCLC). Functional studies indicate the NFIB regulates cell viability and proliferation during transformation.

“The mouse model recapitulates what is seen in human disease. It develops very aggressive lung tumors, which metastasize to sites where metastases are often seen in humans, such as the liver and adrenal glands," Dooley says.

This kind of model allows scientists to follow the disease progression from beginning to end, which can’t normally be done with humans because the fast-spreading disease is often diagnosed very late. Using whole-genome profiling, the researchers were able to identify sections of chromosomes that had been duplicated or deleted in mice with cancer.

"That makes a convincing case where the gene truly plays an important role in human small cell lung cancer," says Barry Nelkin, a professor of oncology at Johns Hopkins University School of Medicine, who was not involved in this research.

“The question, always, with mouse models is whether they can tell you anything about a human disease,” Nelkin says. “Some tell you something, but in others, there may be only a similarity in behavior, and the genetic changes are nothing like what is seen in humans.”

Researchers in Jacks’ lab collaborated with scientists in Matthew Meyerson’s lab at the Dana-Farber Cancer Institute and the Broad Institute to analyze human cancer cells, and found that NFIB is also amplified in human small cell lung tumors.

The NFIB gene codes for a transcription factor, meaning it controls the expression of other genes, so researchers in Jacks’ lab are now looking for the genes controlled by NFIB.

“If we find what genes NFIB is regulating, that could provide new targets for small cell lung cancer therapy,” Dooley says.

Source was published in the Journal Gene & Development. MIT news

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