‘Switch’ could turn off growth of tough childhood cancer
- Researchers at Texas A&M University Health Science Center have discovered a key weakness in one of the toughest childhood cancers, translocation renal cell carcinoma (tRCC), which affects children and young adults.
- The team found that RNA builds “droplet hubs” in cancer cells, acting as command centers to switch on growth-promoting genes, but also created a molecular switch to dissolve these hubs, cutting off tumor growth at its source.
- The researchers used advanced tools such as CRISPR gene editing, SLAM-seq, and proteomics to understand how TFE3 oncofusions hijack RNA to build cancer’s growth hubs, revealing a new angle for therapy development.
- A nanobody-based chemogenetic tool was engineered to dissolve the droplet hubs, halting tumor growth in both lab-grown cancer cells and mouse models, offering a potential new strategy for treating tRCC.
- The discovery has implications beyond tRCC, as many pediatric cancers are also driven by fusion proteins, making this research a promising step towards developing more precise and potentially less toxic therapies for these devastating diseases.
By revealing how RNA builds the “droplet hubs” that drive cancer growth—and how to dismantle them—scientists have discovered a key weakness that could help stop one of the toughest childhood cancers.
In a city, coworking hubs bring people and ideas together. Inside cancer cells, similar hubs form—but instead of fueling progress, they supercharge disease. That’s what researchers at the Texas A&M University Health Science Center (Texas A&M Health) have discovered inside the cells of a rare and aggressive kidney cancer.
Their new study in Nature Communications shows how RNA—normally just a messenger—gets hijacked to build liquid-like “droplet hubs” in the nucleus. These hubs act as command centers, switching on growth-promoting genes.
But the team didn’t stop at observing this—they created a molecular switch to dissolve the hubs on demand, cutting off the cancer’s growth at its source.
The cancer they’re investigating, called translocation renal cell carcinoma (tRCC), affects children and young adults and currently has almost no effective therapies. It is caused by TFE3 oncofusions—hybrid genes formed when chromosomes swap and fuse in the wrong places.
Until now, how these fusion proteins drove such aggressive tumors remained unclear. The researchers found that these fusions enlist RNA as structural scaffolds. Unlike their traditional role as passive messengers, these RNAs now actively assemble droplets, known as condensates, that cluster key molecules together. These droplets become transcriptional hubs—hotspots that switch on cancer-promoting genes.
“RNA itself is not just a passive messenger, but an active player that helps build these condensates,” says Yun Huang, professor at the Texas A&M Health Institute of Biosciences and Technology and senior author.
The researchers also discovered that an RNA-binding protein called PSPC1 acts as a stabilizer, reinforcing the droplets and making them even more powerful engines for tumor growth.
To untangle this hidden process, the team leaned on some of today’s most advanced tools in molecular biology:
- CRISPR gene editing to “tag” fusion proteins in patient-derived cancer cells, letting them track exactly where these proteins go.
- SLAM-seq, a next-generation sequencing method that measures newly made RNA, showing which genes are switched on or off as the droplets form.
- CUT&Tag and RIP-seq to map where the fusion proteins bind DNA and RNA, revealing their precise targets.
- Proteomics to catalog the proteins pulled into the droplets—pinpointing PSPC1 as a key partner.
By layering these techniques, the researchers built the clearest picture yet of how TFE3 oncofusions hijack RNA to build cancer’s growth hubs.
Discovery alone wasn’t enough. The team wanted to know: If the droplets are cancer’s engine, can we shut them down?
To test this, they engineered a nanobody-based chemogenetic tool—essentially a designer molecular switch. Here’s how it works:
- A nanobody (a miniature antibody fragment) is fused with a dissolver protein.
- The nanobody locks onto the cancer-driving fusion proteins.
- When activated by a chemical trigger, the dissolver melts the droplets, breaking the hubs apart.
The result? Tumor growth ground to a halt in both lab-grown cancer cells and mouse models.
“This is exciting because tRCC has very few effective treatment options today,” says Yubin Zhou, professor and director of the Center for Translational Cancer Research.
“Targeting condensate formation gives us a brand-new angle to attack the cancer, one that traditional drugs have not addressed. It opens the door to therapies that are much more precise and potentially less toxic.”
For the research team, the most powerful part of the study wasn’t just watching RNA build these hubs but seeing that they could be dismantled.
“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,” says Lei Guo, research assistant professor at the Institute of Biosciences and Technology.
Because many pediatric cancers are also driven by fusion proteins, the implications extend far beyond tRCC. A tool that can dissolve these condensates could represent a general strategy to cut off cancer’s engine rooms at the source.
tRCC makes up nearly 30% of renal cancers in children and adolescents, but for patients and families, treatment options are limited and outcomes are often poor. This research not only explains how the cancer organizes its growth machinery but also offers a tangible way to stop it.
“This research highlights the power of fundamental science to generate new hope for young patients facing devastating diseases,” Huang adds.
Just like cutting power to a coworking hub halts all the activity inside, dissolving cancer’s “droplet hubs” could shut down its ability to grow. By showing how RNA actively builds these hubs—and by designing a way to dismantle their scaffolding—the researchers have uncovered both a weakness and a new path toward treating one of the toughest childhood cancers.
Source: Texas A&M University
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