NEW LUNG CANCER GENE: THE POWER OF MOUSE MODELS IN UNDERSTANDING HUMAN DISEASE

By René A. Azeez, Honours BSc. Developmental Biology, University of Toronto. July 20, 2011.

                Cancer research faces many obstacles, the least of which is the sheer number of mechanisms by which cancer can arise and proliferate. Because of this and other factors, including the argument that cancer is evolutionarily conserved, it is hard to say with absolute certainty that a singular “cure for cancer” is a feasible goal. However, intuitively it seems that having an understanding of individual cancers and specific targets for treatment would be a more realistic and beneficial outlook. Alison Dooley of the David H. Koch Institute for Cancer Research at MIT is the lead author of a paper entitled “Nuclear Factor I/B is an oncogene in small cell lung cancer” that was published in the July 15 edition of Genes and Development. In the paper it is revealed that researchers have pinpointed a gene which apparently drives the progression of small cell lung cancer (SCLC).

            SCLC is an aggressive cancer accounting for about 15% of lung cancer cases and is often only diagnosed after it has metastasized. SCLC kills over 90% of patients within half a decade of being diagnosed. Previously, SCLC had been poorly characterized at the genomic level. Dr. Dooley and her team used a previously designed mouse model in which the tumor suppressor genes, Trp53 and Rb1, were conditionally deleted to identify genetic alterations that occur during SCLC progression.

            Using multiple techniques to identify genetic alterations in SCLC tumors and metastases, researchers were able to show that although the majority of the genome was surprisingly unaltered from normal cells, there were several high-level focal amplifications and deletions in tumor specimens. Nuclear factor I/B (NFIB) was found to represent a newly identified amplified gene in SCLC tumor cell expression profiles. Researchers were then able to confirm that NFIB amplifications were also seen in human SCLC.

            Knocking out NFIB in human SCLC tumors, researchers were also able to demonstrate that “NFIB is integral to human SCLC cell line viability and/or proliferation, likely depending on the NFIB levels or the cellular context of each individual tumor.” Researchers went further to demonstrate through analyses (transformations, arrays, gene set enrichment analysis) that NFIB seems to have oncogenic (cancer causing) properties.

            Dr. Dooley and her team point out that using a mouse model allowed for tumors to be initiated by defined genetic events and the disease progresses in the absence of smoking induced passenger mutations that could occur in studying the cancer type in humans. They also point out that a wealth of tumor and metastasis samples could be collected from mouse models at different stages giving more insight into the dynamic properties of genetic expression as relates to SCLC. They suggest that future efforts to identify point mutations in mouse SCLC models in conjunction with cross-species analyses would serve to prioritize the daunting number of meaningful mutations being expressed in human SCLC. It is conceivable that this approach would be beneficial in other types of cancers as well.

REFERENCE:

Dooley A. et al. Nuclear Factor I/B is an oncogene in small cell lung cancer. Genes and Development, 2011: (25) 1470-1475.