Gene Fusions and Their Role in Kidney Cancer Development Through Condensate Formation

Recent research from UT Southwestern Medical Center has shed light on how gene fusion mutations drive certain types of kidney cancer by creating abnormal biomolecular condensates that manipulate gene transcription processes. This groundbreaking study, published in the journal Cell, reveals that oncofusion proteins—products of chromosomal translocations—have an enhanced ability to form these condensates within cell nuclei, which in turn alters gene expression patterns and promotes malignancy.

In particular, the study focused on translocations involving the gene for the transcription factor TFE3, commonly fused with other genes such as PRCC, ASPL, or SFPQ in a type of kidney cancer called translocation renal cell carcinoma (tRCC). These fusions are especially prevalent in young patients and account for about 4% of adult kidney cancers. Researchers found that these fusion proteins exhibit a unique propensity to form dynamic condensates, which are compartmentalized networks of proteins and nucleic acids within cells. These structures are known to regulate gene activity efficiently.

The team utilized specialized staining techniques and biochemical experiments to observe that the fusion proteins could recruit key regulators of transcription, notably RNA polymerase II, the enzyme responsible for copying DNA into RNA. The RNA polymerase II's recruitment appears to be driven by specific amino acid compositions in the fusion proteins, which differ from the wild-type TFE3. Modifying these amino acid sequences confirmed their critical role in condensate formation and in capturing the transcription machinery.

Cells harboring mutated TFE3 with increased amino acids that favor condensate formation displayed heightened malignant behaviors, such as increased proliferation and invasiveness. These findings suggest that the fusion proteins promote cancer progression by creating a favorable environment for overactive gene transcription.

Strikingly, the study uncovered that this mechanism of condensate formation and RNA polymerase II recruitment is not unique to TFE3 fusions. By analyzing other oncofusion mutations across various cancers, researchers observed similar transformations, implying a shared molecular pathway that could be exploited for targeted therapies. Disrupting these interactions may pave the way for novel treatments for kidney cancer and potentially other cancers driven by similar fusion proteins.

This discovery highlights a promising avenue for cancer research, focusing on how abnormal protein interactions within condensates influence gene regulation and malignancy. Future work is expected to develop strategies to interfere with these condensate formations and transcriptional hijacking, offering hope for improved therapeutic options.

For more information, see: Heankel Lyons et al, RNA polymerase II partitioning is a shared feature of diverse oncofusion condensates, Cell (2025). DOI: 10.1016/j.cell.2025.04.002