Image: National Cancer Institute |
A
major challenge for cancer biologists is figuring out which among the hundreds
of genetic mutations found in a cancer cell are most important for driving the
cancer’s spread.
Using
a new technique called whole-genome profiling, Massachusetts Institute of
Technology (MIT) scientists have now pinpointed a gene that appears to drive
progression of small cell lung cancer, an aggressive form of lung cancer
accounting for about 15% of lung cancer cases.
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 paper
describing the finding in Genes and Development.
Small
cell lung cancer kills about 95% of patients within five years of diagnosis;
scientists do not yet have a good understanding of which genes control it.
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, p53 and Rb.
“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.
They
found extra copies of a few short stretches of DNA, including a segment of
chromosome 4 that turned out to include a single gene called Nuclear Factor I/B
(NFIB). This is the first time NFIB has been implicated in small cell lung
cancer, though it has been seen in a mouse study of prostate cancer. The gene’s
exact function is not known, but it is involved in the development of lung
cells.
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.
