(L to R) Co-corresponding author Richard Kriwacki, PhD, St. Jude Department of Structural Biology, co-first authors Srinidhi Varadharajan and Amir Arabzade, PhD, both of the St. Jude Department of Developmental Neurobiology, co-author Aaron Phillips, PhD, St. Jude Department of Structural Biology and co-corresponding author Stephen Mack, PhD, St. Jude Department of Developmental Neurobiology.
A study looking at the biophysical properties of an abnormal protein driving cancer cells is giving scientists new therapeutic clues for how to treat ependymoma, the third most common childhood brain tumor. St. Jude Children’s Research Hospital scientists were studying how the fusion protein ZFTA–RELA, implicated in 95% of ependymomas in the brain cortex, drives disease. Results of the study demonstrate that disordered regions of the fusion protein cause the formation of droplets within cells called condensates. The researchers revealed that these “membraneless organelles” are essential for ependymoma development. The findings were published today in Nature Cell Biology.
“Ependymomas have had essentially the same treatments for 30 years,” said co-corresponding author Stephen Mack, PhD, St. Jude Department of Developmental Neurobiology. “By describing how this abnormal fusion protein drives this deadly brain tumor, we are paving the road to look for new targeted therapies.”
The scientists started their study by examining the different regions of the ZFTA–RELA fusion protein. They found that the ZFTA portion, which binds DNA directly, was required for cancer development. The RELA portion contains a highly disordered region, meaning it lacks a rigid structure and can move flexibly, and was necessary for condensate formation. Condensates are a way cells organize molecules responsible for carrying out various tasks.
When the disordered RELA region was absent, condensates did not form, and ependymoma did not develop in mice. However, when the scientists swapped the RELA portion with other, unrelated disordered protein regions, the novel fusions still formed condensates, driving the oncogene expression that led to brain tumor development.
“Our findings strengthen the view that condensate formation should be considered as a driving mechanism for oncogenic fusion proteins in general,” said co-corresponding author Richard Kriwacki, PhD, St. Jude Department of Structural Biology. “Especially for those that alter chromatin biology.”
Condensates present a new therapeutic frontier
In ependymoma, the condensates assemble the molecules responsible for gene expression. Inside the condensates, the ZFTA portion of the fusion protein guides the complex to the DNA encoding certain oncogenes. The researchers showed that this abnormal process is necessary for ependymoma formation, suggesting it could be disrupted for therapeutic effect.
“Fusion proteins such as ZFTA–RELA are challenging drug targets, but our findings provide an indirect approach,” Kriwacki added. “Instead of focusing on this fusion protein, we can now start identifying its interacting partners within condensates, examining which are essential for tumor formation and targeting those.”
While the work was done in ependymoma, other cancers driven by other fusion proteins may have a similar vulnerability.
“We discovered a novel mechanism for assembling molecules that underlies the formation of a deadly brain tumor,” Mack said. “By understanding these aberrant condensates, we may have found a new place to look for therapeutic interventions for cancers driven by fusion oncoproteins.”
Authors and funding
The study’s co-first authors are Amir Arabzade, Hazheen K. Shirnekhi and Srinidhi Varadharajan, all of St. Jude. The study’s other authors are Siri Ippagunta, Aaron H. Phillips, Nic Laboe, David Baggett, Wahifuzzaman Fnu, Minjeong Jo, Tuyu Zheng, D. Gee, Erik Emanus, Amanda Bland, Alisha Kardian, Amelia Hancock, Swarnendu Tripathi, Abbas Shirinifard, Kim Lowe, Ali Khalighifar, Rebecca Petersen, Sharon King, Daniel Stabley, Aaron Pitre, George Campbell, Cheon-Gil Park, W. Toler Freyaldenhoven, Bappaditya Chandra, Youlin Xia, Erik Bonten, Anushree Achari, Suresh Kandikonda, Alex Carisey, David Ellison and Kelsey Bertrand, St. Jude; Devesh Bhimsaria, Indian Institute of Technology, Roorkee, India; and Benjamin Deneen, Baylor College of Medicine, Houston, TX.
The study was supported by grants from the National Cancer Institute (P30CA021765, R01NS128184, R01CA280203, R01CA284455, U01CA281823, R01CA246125 and U54CA243124), the Department of Defense (IDEA CA220510 and IMPACT CA220247), the National Institutes of Health (GM120625 and NS108376), the St. Jude Children’s Research Hospital Research Collaborative on Transcription Regulation in Pediatric Cancer, Alex’s Lemonade Stand Foundation (‘A’ Award), the National Brain Tumor Society, the CERN Foundation, the Robert Connor Dawes Foundation and ALSAC, the fundraising and awareness organization of St. Jude. The work was also supported by the Cell & Tissue Imaging Center, Center for Bioimage Informatics, Biostatistics Shared Resource and Biomolecular NMR Center at St. Jude.
St. Jude Children's Research Hospital
St. Jude Children’s Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. As the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, St. Jude advances groundbreaking research and shares its discoveries worldwide to accelerate progress in pediatric medicine. Treatments developed at St. Jude have helped increase overall childhood cancer survival rates from 20% to 80% since the hospital opened more than 60 years ago. Through collaboration and innovation, St. Jude is working to ensure that children everywhere have access to the best possible care. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.