Researchers at the Spanish National Cancer Research Centre (CNIO) have made progress in the fight against glioblastoma. They found that a protein, RanBP6, regulates a receptor that has a role in human development and cancer, epidermal growth factor receptor (EGFR). Reporting in Nature Communications, they found that by silencing RanBP6, glioma growth was promoted because EGFR expression was increased.
Of the roughly 100,00 new cases of malignant brain tumors that are diagnosed every year, glioblastoma is the deadliest and most common type of adult primary central nervous system tumor. The genome of glioma cells has been found to be incredibly complicated, however, and the effect of the many genetic mutations that arise is not known.
The Seve Ballesteros Foundation-CNIO Brain Tumor Group, headed by Massimo Squatrito, in collaboration with the laboratory of Ingo Mellinghoff at the Memorial Sloan-Kettering Cancer Center in New York, has now uncovered a novel mechanism that contributes to preventing glioblastoma development.
EGFR has a critical role in normal development, as well as in human cancer, making it a major drug target in cancer therapeutics. Dysfunctional activation of EGFR can cause tumors to grow. It has been suggested that increases in gene copy numbers and gain-of-function mutations are to blame, but problems in the regulation of EGFR can also be a cause.
Study co-lead authors Barbara Oldrini and Wan-Ying Hsieh found a new player in EGFR regulation. An uncharacterized protein, RanBP6, was identified as a modulator of EGFR expression. RanBP6 is a member of the importin family that regulates the import of signal transducer and activator of transcription 3 (STAT3) to the nucleus. When RanBP6 is halted, STAT3 nuclear translocation is impaired; then there is less transcription of EGFR, increasing EGFR pathway output.
"Our studies showed for the first time that STAT3 is a direct inhibitor of EGFR expression. I believe this has important clinical implications: STAT3 inhibitors are currently being investigated for the treatment of glioblastoma and other tumor types. Inhibiting STAT3 signaling could lead to an undesired activation of EGFR signaling,” explained Massimo Squatrito.
Some deletions of RanBP6 were found in some glioblastoma patients. Silencing RanBP6 caused growth glioma in a mouse glioma model, due to an upregulation of EGFR.
"Our results provide an example of EGFR deregulation in cancer through silencing of components of the nuclear import pathway. We have identified a new link between the Ran-GTPase nuclear transport pathway and key cancer signaling pathways which warrant further study as inhibitors targeting nuclear transporters enter clinical evaluation as cancer therapeutics,” concluded Barbara Oldrini.
This group has been working to treat brain tumors for years; learn more about their lab from the video.