Data from TFE3 Xp11.2 Translocation Renal Cell Carcinoma Mouse Model Reveals Novel Therapeutic Targets and Identifies GPNMB as a Diagnostic Marker for Human Disease

Abstract

<div>Abstract<p>Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix–loop–helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the <i>PRCC-TFE3</i> transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that <i>Gpnmb</i> (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that <i>GPNMB</i> is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical <i>in vivo</i> model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC.</p>Implications:<p>Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.</p></div>

An engineered tumor organoid model reveals cellular identity and signaling trajectories underlying translocation RCC

“…These cells were marked by expression of known markers of tRCC, such as GPNMB (Supplementary Fig. 3C) (4) and CTSK (Supplementary Fig. 3D) (27), strongly suggesting that this the population that transformed to tRCC.…”

“…These fusions make tRCC fundamentally different from the majority of RCC, which typically harbor a high mutational load and numerous copy number alterations. Using mouse models, tubular epithelial cells were shown to be permissive to tRCC formation upon expression of the oncogenic fusion (4). Large genome sequencing efforts, however, revealed recurrent genetic alterations in tRCC that could serve as tumor drivers.…”