In a groundbreaking study led by researchers at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health, scientists have uncovered crucial molecular mechanisms underlying a rare and aggressive form of kidney cancer known as translocation renal cell carcinoma (tRCC). This malignancy develops through chromosomal rearrangements that fuse the gene TFE3 with other distinct partner genes, giving rise to novel fusion proteins that significantly alter cellular behavior.

Normal TFE3 protein seems diffuse all through a cell (left), whereas the TFE3 fusion proteins present in a uncommon kidney cancer type tiny liquid droplets close to the cell’s DNA, where they regulate cancer-promoting genes. Credit: Cell Reports (2025). DOI: 10.1016/j.celrep.2025.115539 Scientists report that they’ve realized how sure combos of rearranged genes can promote the development of a uncommon sort of kidney cancer. The study was led by investigators on the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health. The researchers demonstrated that proteins created from these rearranged, so-called fusion genes type tiny liquid Read More

TFE3-rearranged renal cell carcinoma (TFE3-RCC) lacks clearly defined diagnostic and therapeutic targets. SV2B, a TFE3 target gene, promotes TFE3-RCC progression by activating the NF-κB pathway. Targeted inhibition with padsevonil or Withaferin A effectively suppresses tumor progression. This study establishes SV2B as a novel diagnostic biomarker and validates SV2B-NF-κB signaling as a therapeutic target for TFE3-RCC. Abstract TFE3-rearranged renal cell carcinoma (TFE3-RCC) represents an aggressive subtype of renal cancer characterized by a poor prognosis, yet lacking clearly defined diagnostic and therapeutic targets. Here, the study demonstrates that synaptic vesicle protein 2B (SV2B) is a potential diagnostic marker and therapeutic target for TFE3-RCC. SV2B , identified as a TFE3 target gene, is significantly upregulated in TFE3-RCC and displays high diagnostic accuracy for this subtype. Functionally, SV2B enhances the proliferation, migration, and invasion of TFE3-RCC cells. Mechanistically, SV2B competes with RELA/NFKB1 for binding to the E3 ligase HERC2, preventing their degradation and activating the NF-κB pathway. The drug padsevonil, targeting SV2B, selectively inhibits the growth of TFE3-RCC cells and organoids, similar to the NF-κB inhibitor Withaferin A. Clinically, RELA/NFKB1 expression positively correlates with SV2B levels but negatively with HERC2 expression, confirming the activation of TFE3-SV2B-NF-κB axis in TFE3-RCC. These findings establish SV2B as a novel diagnostic biomarker for TFE3-RCC and validate SV2B-NF-κB signaling as a therapeutic target, providing potential strategies for managing TFE3-RCC.