MADRID, 21 (EUROPA PRESS)
Australian researchers have used an innovative whole-genome screening method to identify genes, and their encoded proteins, that play critical roles in preventing the development of lymphoma, revealing new potential treatment targets for these blood cancers.
The study, published in Nature Communications, has identified a group of proteins known as the GATOR1 complex as essential tumor suppressors. The GATOR1 complex normally functions as a brake on cell growth by regulating pathways that control cell growth and metabolism. When GATOR1 components are missing or defective, this protective mechanism fails, allowing cells to grow uncontrollably.
The research is a collaboration between the Olivia Newton-John Cancer Research Institute (ONJCRI), WEHI, and the Peter MacCallum Cancer Centre (Australia). The team used sophisticated preclinical models of aggressive lymphoma to systematically evaluate the function of all known genes in this complex. Their comprehensive screening approach revealed that when any of the GATOR1 genes is missing, lymphoma development is dramatically accelerated, identifying the GATOR1 complex as a crucial suppressor of blood cancer development.
“The best thing about performing a well-designed CRISPR screen is that you always find something. Our unbiased screening approach analyzed all genes, rather than just a subset. By not limiting our search to known pathways, we found both expected and unexpected tumor suppressor genes and pathways, such as GATOR1,” explained co-senior author Margaret Potts.
Surprisingly, existing drugs that target the same cellular pathways normally controlled by GATOR1 were highly effective in slowing lymphoma growth in preclinical models of GATOR1 deficiency. These drugs have so far had limited success in cancer treatment, which may be because researchers have been unable to identify which patients would respond well to these therapies. "Our paper begins the exploration of this precision medicine opportunity," Potts noted.
Professor Marco Herold, Executive Director of ONJCRI, Director of the La Trobe School of Oncology Medicine, and senior author of the paper, stated that the preclinical lymphoma model is driven by high levels of the MYC oncogene, an abnormality found in approximately 70 percent of all human cancers. "When GATOR1 is missing, a critical brake that normally slows MYC-driven malignancy is removed," he added.
"This exciting discovery provides new insight into the development and sustained spread of cancer, which we hope will inform the development of more effective and targeted cancer treatments," Herold said.
According to the Global Cancer Observatory, more than 630,000 new cases of lymphoma were reported worldwide in 2022, highlighting the urgent need to better understand the molecular mechanisms that drive this disease.
