TY - JOUR
T1 - TFE3 XP11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease
AU - Baba, Masaya
AU - Furuya, Mitsuko
AU - Motoshima, Takanobu
AU - Lang, Martin
AU - Funasaki, Shintaro
AU - Ma, Wenjuan
AU - Sun, Hong Wei
AU - Hasumi, Hisashi
AU - Huang, Ying
AU - Kato, Ikuma
AU - Kadomatsu, Tsuyoshi
AU - Satou, Yorifumi
AU - Morris, Nicole
AU - Karim, Baktiar O.
AU - Ileva, Lilia
AU - Kalen, Joseph D.
AU - Krisna, Luh Ade Wilan
AU - Hasumi, Yukiko
AU - Sugiyama, Aiko
AU - Kurahashi, Ryoma
AU - Nishimoto, Koshiro
AU - Oyama, Masafumi
AU - Nagashima, Yoji
AU - Kuroda, Naoto
AU - Araki, Kimi
AU - Eto, Masatoshi
AU - Yao, Masahiro
AU - Kamba, Tomomi
AU - Suda, Toshio
AU - Oike, Yuichi
AU - Schmidt, Laura S.
AU - Marston Linehan, W.
N1 - Funding Information:
M. Baba reports receiving commercial research grant from Ono Pharmaceutical Co. Ltd and Bristol-Myers Squibb K.K. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We thank Maria Merino for informative in-depth discussions of comparative human/mouse normal and abnormal histopathology, Nobuko Irie for excellent technical support and acknowledge the support provided to us by the University of Texas Southwestern O'Brien Kidney Research Core Center and Peter Igarashi for Cadherin 16 (KSP)-Cre transgenic mice. pRosa26-DEST was a gift from Nick Hastie and Peter Hohenstein (Addgene plasmid # 21189). M. Baba was supported, in part, by a JSPS KAKENHI Grant-in-Aid for Scientific Research (S), (#18H05284, #26221309), Grant-in-Aid for Scientific Research (B; # 15H04975, # 18H02938), Grant-in-Aid for Challenging Research (Exploratory; # 18K19619, #18K19553), Grant-in -Aid for Scientific Research on Innovative Areas (#16H06276), Grant-in-Aid for Scientific Research (C; #18K09140), Novartis Research Grant, a Research grant from Ono Pharmaceutical Co. Ltd and Bristol-Myers Squibb K.K. Grant, the Joint Usage/Research Center Program of the Advanced Medical Research Center, Yokohama City University (Yokohama, Japan), and the program of the Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University (Kumamoto, Japan). M. Furuya was supported by JSPS KAKENHI, Grant-in-Aid for Scientific Research (C; #17K08745). T. Motoshima was supported by JSPS KAKENHI, Grant-in-Aid for Scientific Research (C; #16K11013) and AKUA (Asahi Kasei pharma Urological Academy) Research Grant. T. Kadomatsu was supported by JSPS KAKENHI, Grant-in-Aid for Scientific Research (C; #18K07236). H. Hasumi was supported by JSPS KAKENHI, Grant-in-Aid for Scientific Research (C; #16K11020). Y. Nagashima was supported by JSPS KAKENHI, Grant-in-Aid for Scientific Research (C; #17K11162). T. Kamba was supported by JSPS KAKENHI, Grant-in-Aid for Scientific Research (C; #18K09140). T. Suda was supported by a JSPS KAKENHI Grant-in-Aid for Scientific Research (S), (#18H05284, #26221309), and the National Medical Research Council grant of Singapore Translational Research Investigator Award (NMRC/STaR/0019/2014). Y. Oike was supported in part by a JSPS KAKENHI Grant-in-Aid for Challenging Research (Exploratory; # 18K19519). This research was supported, in part, by the Intramural Research Program of NIH, Frederick National Laboratory, Center for Cancer Research. This project has been funded, in part, with Federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85071055962&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-18-1235
DO - 10.1158/1541-7786.MCR-18-1235
M3 - Article
C2 - 31043488
AN - SCOPUS:85071055962
SN - 1541-7786
VL - 17
SP - 1613
EP - 1626
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
IS - 8
ER -
