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Silencing a silencer
Ludwig researchers reveal a new mechanism by which a mutant receptor propels the growth of an aggressive brain cancer
February 6, 2014, New York, NY - A Ludwig Cancer Research study has unveiled a novel signaling cascade in cells that appears to contribute uniquely to the malignancy of glioblastoma multiforme (GBM), the deadliest and most common form of brain cancer in adults. The study sheds new light on the pathology of GBM and clears a path to the identification of potential drug targets.
Published in the current issue of Cancer Research, the study reveals how a mutated epidermal growth factor receptor (EGFR) named ΔEGFR (also known as EGFRvIII) suppresses a regulator of gene expression, microRNA-9 (miR-9), to boost tumor cell proliferation. Led by Ludwig researchers Frank Furnari and Webster Cavenee and postdoctoral fellow, German Gomez, at the University of California, San Diego, the study shows that this occurs because the suppression of miR-9 boosts the production of a transcription factor known as FOXP1. The researchers also find that the elevated expression of FOXP1 in glioblastoma tumors is associated with poor patient survival.
“miR-9 is clearly expressed at much lower levels when this mutant receptor is present,” says Furnari. “We have uncovered a novel way in which this mutant receptor controls the malignancy of glioblastoma tumors.”
ΔEGFR, the EGFR mutant most commonly associated with GBM, promotes many aspects of that cancer’s malignancy, including its invasiveness and resistance to therapy. miR-9, meanwhile, binds to the messenger RNA that encodes FOXP1 and so shuts down its translation into a protein. The researchers find that ΔEGFR’s suppression of miR-9 occurs through a known signaling pathway that involves the proteins Ras, PI 3-kinase and AKT.
They show that the silencing of miR-9 induced by this signal promotes tumor growth. Conversely, enhanced expression of miR-9 suppresses FOXP1—and has the opposite effect. “Only ΔEGFR seems to have this effect on miR-9,” says Furnari. “It appears to have a personality all its own in this regard.”
The study suggests FOXP1 is a cancer-promoting gene in glioblastoma. Neither miR-9 nor FOXP1 were previously known to play a role in regulating the growth of glioblastoma tumors. Furnari, Cavenee and Gomez are now working with other Ludwig researchers to identify which genes in particular are affected by the enhanced expression of FOXP1. Their hope is that this will yield new drug targets for the treatment of glioblastoma.
This study was supported by funding from the Ludwig Institute for Cancer Research, the American Brain Tumor Association, the James S. McDonnell Foundation, the National Foundation for Cancer Research and the AIRC.
About Ludwig Cancer Research
Ludwig Cancer Research is an international collaborative network of acclaimed scientists with a 40-year legacy of pioneering cancer discoveries. Ludwig combines basic research with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.5 billion in life-changing cancer research through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers.
Frank Furnari is a senior investigator at the Ludwig Institute for Cancer Research, as well as a professor within the University of California, San Diego’s department of pathology. Web Cavenee is the director of the Ludwig Institute for Cancer Research San Diego and a distinguished professor at the University of California, San Diego. For more information on their research, click here.