Scientists at Texas A&M University Health Science Center have discovered that RNA forms droplet-like hubs in translocation renal cell carcinoma, activating tumor genes. By developing a molecular switch to dissolve these hubs, they halted cancer growth in lab and mouse models. The findings, published in Nature Communications, offer a new approach for treating this aggressive pediatric cancer.
Translocation renal cell carcinoma (tRCC) is a rare and aggressive kidney cancer that primarily affects children and young adults, representing nearly 30% of renal cancers in this group. It lacks effective treatments and stems from TFE3 oncofusions, abnormal hybrid genes formed by chromosome breaks and fusions. Researchers at Texas A&M focused on understanding how these fusions make tRCC so aggressive.
Their study revealed that RNA, usually a messenger for genetic instructions, is hijacked to build liquid-like 'droplet hubs' in the cell nucleus. These condensates act as command centers, clustering molecules to activate growth-related genes. An RNA-binding protein called PSPC1 stabilizes these droplets, enhancing tumor formation. 'RNA itself is not just a passive messenger, but an active player that helps build these condensates,' said Yun Huang, PhD, professor at the Texas A&M Health Institute of Biosciences and Technology and senior author.
To map this process, the team employed advanced tools including CRISPR gene editing to track fusion proteins, SLAM-seq for measuring new RNA, CUT&Tag and RIP-seq to identify binding sites, and proteomics to catalog droplet proteins. This revealed how TFE3 oncofusions enlist RNA as a structural framework for transcriptional hubs.
Beyond observation, the researchers engineered a nanobody-based chemogenetic tool—a designer switch fusing a miniature antibody with a dissolver protein. When chemically triggered, it targets fusion proteins and melts the droplets, stopping tumor growth in patient-derived cells and mouse models. 'This is exciting because tRCC has very few effective treatment options today,' said Yubin Zhou, MD, PhD, professor and director of the Center for Translational Cancer Research. 'Targeting condensate formation gives us a brand-new angle to attack the cancer.'
The approach could extend to other pediatric cancers driven by fusion proteins, providing a precise, potentially less toxic therapy. 'By mapping how these fusion proteins interact with RNA and other cellular partners, we are not only explaining why this cancer is so aggressive but also revealing weak spots that can be therapeutically exploited,' said Lei Guo, PhD, research assistant professor. The study was published in Nature Communications on October 22, 2025.