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

Abstract

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 PRCC-TFE3 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 Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB 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 in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC. Implications: 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.

Integrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma

“…4A and Supplementary Data 5 ). Among them, GPNMB , HIF1A , MET , and BIRC7 , which were previously reported to have higher expression in tRCC 16 , 17 , were also upregulated in our TFE3 -tRCC cohort (Supplementary Figure 8A). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified that lysosomal, autophagy, and innate immunity pathways were significantly upregulated in TFE3 -tRCC (Fig.…”

Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity

“…To investigate roles of ANGPTL2 in development and progression of tRCC, we generated Chd16-Cre/ Rosa LSL-PRCC-TFE3/+ mice that specifically induce the PRCC-TFE3 fusion gene in renal tubular epithelial cells (Supplemental Fig. S1A; Baba et al 2019;Kurahashi et al 2019). Chd16-Cre/Rosa LSL-PRCC-TFE3/+ mice developed renal cell carcinoma characterized by dilated renal tubules and cyst formation by 40 wk of age, with an incidence of 100%, and their median survival time was 344 d. To evaluate ANGPTL2 function in renal cancer progression, we crossed Chd16-Cre/Rosa LSL-PRCC-TFE3/+ mice with ANGPTL2 mutant mice (either Angptl2 −/− or Angptl2 F/F mice) to achieve ANGPTL2 deficiency in either the whole body or specifically in renal tubular epithelial cells, respectively ( Fig.…”

Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

“…Prior case series have suggested that tRCC has a demographic profile that is distinct from more common subtypes of kidney cancer, with a younger age at diagnosis, advanced stage at presentation, and a female predominance [3][4][5] . Biologically, tRCCs are driven by activating gene fusions involving transcription factors in the MiT/TFE gene family [6][7][8][9][10][11][12] . There are currently no molecularly-targeted therapies specific to tRCC and effective treatments for this aggressive cancer remain a major unmet medical need.…”