Cancer Researchers Identify Factors That Drive Melanoma Metastasis

Cancer researchers have traced a molecular pathway that cycles melanoma cells between modes that favor growth of the primary tumor (progression) and modes that favor invasion of other parts of the body (metastasis).

Cancer is characterized by uncontrolled growth of cells, but if uncontrolled growth was the only problem then cancer cells would be easily treated with surgery in most cases. What makes cancer deadly is its tendency to invade tissue and migrate to other regions of the body. Metastatic melanoma is one of the most aggressive and difficult to treat of all cancer types.

Melanoma is a heterogeneous cancer, made up of many cellular populations that differ in their ability to induce tumor growth or invasion throughout the body. These populations have been found to switch back and forth to drive invasion and progression. This process appears to be controlled by opposing action of two genes, MITF (Microphthalmia-associated transcription factor) and BRN2 (POU class 3 homeobox 2).

Investigators at Queensland University of Technology reported in a paper published in the January 14, 2017, online edition of the journal EBiomedicine that the NFIB (nuclear factor I B) transcription factor was a novel downstream effector of BRN2 function in melanoma cells linked to the migratory and invasive characteristics of these cells. Furthermore, the function of NFIB appeared to drive an invasive phenotype through an epigenetic mechanism achieved via the upregulation of the polycomb group protein EZH2 (Enhancer of zeste homolog 2).

"BRN2 function reduces MITF expression to slow down proliferation and put the cells into invasive mode," said senior author Dr. Aaron Smith, lecturer in the school of biomedical science at Queensland University of Technology. "Our project has identified a pathway that allows BRN2 to do this, firstly by increasing the expression of another regulatory factor called NFIB that further controls an invasive program in these cells."

"An important target of NFIB is an enzyme called EZH2 which then produces global (wide ranging) changes to the cells activity. EZH2 favors the expression of invasive genes and also turns "off" MITF to prevent proliferation, further re-enforcing the invasive capability of the tumor cells", said Dr. Smith. "We have evidence the NFIB-EZH2 pathway may also underpin metastasis of other cancer types as well such as lung cancer. The good news is there are drugs to chemically inhibit EZH2 which are already in pre-clinical trials and which could be used to block the invasion."