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TFE3 Xp11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease

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

  2. Author Address

    International Research Center for Medical Sciences, Kumamoto University., Pathology, Yokohama City University Graduate School of Medicine., Gradiate School of Medical Science, Kumamoto University., Urologic Oncology Branch, National Cancer Institute, National Institutes of Health., Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases., Urology, Yokohama City University Graduate School of Medicine., Urologic Oncology Branch, National Cancer Institute., Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University., 1. Division of Genomics and Transcriptomics, Joint Research Center for Human Retrovirus Infection, Kumamoto University., Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute., Pathology/Histotechnology Laboratory, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute., Small Animal Imaging Program, NIH NCI., Small Animal Imaging Program, Frederick National Laboratory for Cancer Research., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute., DSK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine., Department of Uro-Oncology, Saitama Medical University International Medical Center., Surgical Pathology, Tokyo Women 39;s Medical University., Department of Diagnostic Pathology, Kochi Red Cross Hospital., Institute of Resource Development and Analysis, Kumamoto University., Dept. of Urology, Kyushu University., Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute linehanm@mail.nih.gov.,
    1. Year: 2019
    2. Date: AUG
    3. Epub Date: 2019 05 01
  2. Journal: Molecular cancer research : MCR
    1. 17
    2. 8
    3. Pages: 1613-1626
  4. Type of Article: Article
  5. ISSN: 1541-7786
  1. 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 immunohistochemical 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 as 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 renal cell carcinoma. Implications: Key findings from studies with this preclinical mouse model of TFE-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 renal cell carcinoma. Copyright ©2019, American Association for Cancer Research.

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External Sources

  1. View Full Text
  2. DOI: 10.1158/1541-7786.MCR-18-1235
  3. PMID: 31043488
  4. View record in Web of Science®
  5. WOS: 000478021800003
  6. PII : 1541-7786.MCR-18-1235

Library Notes

  1. Fiscal Year: FY2018-2019
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