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

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  • Masaya Baba
    1Laboratory of Cancer Metabolism, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
  • Mitsuko Furuya
    3Department of Molecular Pathology, Yokohama City University, Yokohama, Japan.
  • Takanobu Motoshima
    4Department of Urology, Kumamoto University, Kumamoto, Japan.
  • Martin Lang
    2Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Shintaro Funasaki
    1Laboratory of Cancer Metabolism, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
  • Wenjuan Ma
    1Laboratory of Cancer Metabolism, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
  • Hong-Wei Sun
    5Biodata Mining and Discovery Section, NIAMS, NIH, Bethesda, Maryland.
  • Hisashi Hasumi
    2Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Ying Huang
    2Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Ikuma Kato
    3Department of Molecular Pathology, Yokohama City University, Yokohama, Japan.
  • Tsuyoshi Kadomatsu
    7Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan.
  • Yorifumi Satou
    8Laboratory of Retroviral Genomics and Transcriptomics, International Research Center for Medical Sciences (IRCMS), Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
  • Nicole Morris
    9Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
  • Baktiar O. Karim
    10Pathology/Histotechnology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
  • Lilia Ileva
    11Small Animal Imaging Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
  • Joseph D. Kalen
    11Small Animal Imaging Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
  • Luh Ade Wilan Krisna
    1Laboratory of Cancer Metabolism, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
  • Yukiko Hasumi
    2Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Aiko Sugiyama
    12DSK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
  • Ryoma Kurahashi
    4Department of Urology, Kumamoto University, Kumamoto, Japan.
  • Koshiro Nishimoto
    13Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan.
  • Masafumi Oyama
    13Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan.
  • Yoji Nagashima
    14Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.
  • Naoto Kuroda
    15Department of Pathology, Kochi Red Cross Hospital, Kochi, Japan.
  • Kimi Araki
    16Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
  • Masatoshi Eto
    17Department of Urology, Kyushyu University, Fukuoka, Japan.
  • Masahiro Yao
    6Department of Urology, Yokohama City University, Yokohama, Japan.
  • Tomomi Kamba
    4Department of Urology, Kumamoto University, Kumamoto, Japan.
  • Toshio Suda
    18Laboratory of Stem Cell Regulation, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
  • Yuichi Oike
    7Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan.
  • Laura S. Schmidt
    2Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • W. Marston Linehan
    2Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

書誌事項

公開日
2019-08-01
資源種別
journal article
DOI
  • 10.1158/1541-7786.mcr-18-1235
公開者
American Association for Cancer Research (AACR)

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説明

<jats:title>Abstract</jats:title> <jats:sec> <jats:title/> <jats: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 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Implications:</jats:title> <jats: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.</jats:p> </jats:sec>

収録刊行物

  • Molecular Cancer Research

    Molecular Cancer Research 17 (8), 1613-1626, 2019-08-01

    American Association for Cancer Research (AACR)

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