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

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.

Molecular cancer research : MCR. 2019 May 01 [Epub ahead of print]

Masaya Baba, Mitsuko Furuya, Takanobu Motoshima, Martin Lang, Shintaro Funasaki, Wenjuan Ma, Hong-Wei Sun, Hisashi Hasumi, Ying Huang, Ikuma Kato, Tsuyoshi Kadomatsu, Yorifumi Satou, Nicole Morris, Baktiar O Karim, Lilia Ileva, Joseph D Kalen, Luh Ade Wilan Krisna, Yukiko Hasumi, Aiko Sugiyama, Ryoma Kurahashi, Koshiro Nishimoto, Masafumi Oyama, Yoji Nagashima, Naoto Kuroda, Kimi Araki, Masatoshi Eto, Masahiro Yao, Tomomi Kamba, Toshio Suda, Yuichi Oike, Laura S Schmidt, W Marston Linehan

Laboratory of Cancer Metabolism, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan. ., Department of Molecular Pathology, Yokohama City University, Yokohama, Japan., Department of Urology, Kumamoto University, Kumamoto, Japan., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Laboratory of Cancer Metabolism, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan., Biodata Mining and Discovery Section, NIAMS, NIH, Bethesda, Maryland., Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan., Laboratory of Retroviral Genomics and Transcriptomics, International Research Center for Medical Sciences (IRCMS), Center for AIDS Research, Kumamoto University, Kumamoto, Japan., Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland., Pathology/Histotechnology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland., Small Animal Imaging Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland., DSK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan., Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan., Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan., Department of Pathology, Kochi Red Cross Hospital, Kochi, Japan., Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan., Department of Urology, Kyushyu University, Fukuoka, Japan., Department of Urology, Yokohama City University, Yokohama, Japan., Laboratory of Stem Cell Regulation, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. .

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