Leveraging First Mouse Model Reproducing Human Translocation Renal Cell Carcinoma to Investigate Molecular Mechanisms

A particularly aggressive and challenging kidney cancer subtype is translocation renal cell carcinoma (tRCC). tRCC predominantly affects children and adolescents and is incurable when metastatic. Importantly, tRCC is an orphan disease without specific therapies. tRCC is characterized by chromosomal translocations of the Microphtalmia (MiT) transcription factors, which are key regulators of lysosome biogenesis and autophagy. The most common translocated MiT gene is TFE3 and the most common partner is ASPSCR1. Our current understanding for how these chimeric fusion proteins promote tumorigenesis points to aberrant constitutive overexpression of transcriptionally active MiT transcription factors, which are characterized by a N’ transactivation domain (N-TAD), a basic helix-loop-helix (bHLH) domain implicated in DNA binding, and a leucine zipper dimerization domain. However, these studies are largely based on in vitro assays, and the contribution of TFE3 to tRCC tumorigenesis remains unknown. Addressing these questions has been hampered by a lack of tRCC animal models reproducing the human disease. To overcome this barrier, we have generated a mouse model based on the most common translocation (Prakasam et al., JCI 2024). In preliminary data we show that conditional ASPSCR1-TFE3 overexpression using a Sglt2-Cre driver leads to tRCC undistinguishable from human tRCC. Interestingly, when driven by Pax8-Cre, which we previously showed drives clear cell RCC (which is believed to arise from the same cells as tRCC), ASPSCR1-TFE3 induces cellular morphological changes typical of tRCC, but without increasing proliferation. Furthermore, constitutive ASPSCR1-TFE3 expression in the Pax8 lineage abolishes glomeruli, which are essential for kidney function, resulting in perinatal death. These data show that cell fate and proliferative functions of ASPSCR1-TFE3 are not necessarily linked and provide two experimental contexts in which to dissect ASPSCR1-TFE3 function. Here, we propose to leverage this innovative tRCC mouse model, the first animal model to faithfully recapitulate human tRCC, to investigate the molecular mechanism of tRCC tumorigenesis. Building upon preliminary data that implicates for the first time TFE3 DNA-binding for tumorigenesis, we propose to dissect the function of the N-TAD in tumorigenesis and cell fate programs. In addition, we will explore how autophagy, which is induced in tRCC, contributes to tRCC development. Finally, we will use the ASPSCR1-TFE3 model to develop new therapeutic opportunities. If successful, these studies leveraging an innovative mouse model will provide fundamental understanding about tRCC pathogenesis and present opportunities for therapeutic intervention addressing a significant unmet medical need. Project Number: 1R01CA289885-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: James Brugarolas | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $596,501 | Activity Code: R01 | Study Section: Gene Regulation in Cancer Study Section[GRIC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296102