TFE3 XP11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease

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 KurahashiKoshiro 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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1613-1626
Number of pages14
JournalMolecular Cancer Research
Volume17
Issue number8
DOIs
Publication statusPublished - Aug 1 2019

Fingerprint

Renal Cell Carcinoma
Therapeutics
Biomarkers
Kidney
Transcription Factors
Cathepsin K
Leucine Zippers
Molecular Pathology
Kidney Neoplasms
Receptor Protein-Tyrosine Kinases
Dimerization
Transgenes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

TFE3 XP11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease. / Baba, Masaya; Furuya, Mitsuko; Motoshima, Takanobu; Lang, Martin; Funasaki, Shintaro; Ma, Wenjuan; Sun, Hong Wei; Hasumi, Hisashi; Huang, Ying; Kato, Ikuma; Kadomatsu, Tsuyoshi; Satou, Yorifumi; Morris, Nicole; Karim, Baktiar O.; Ileva, Lilia; Kalen, Joseph D.; Krisna, Luh Ade Wilan; Hasumi, Yukiko; Sugiyama, Aiko; Kurahashi, Ryoma; Nishimoto, Koshiro; Oyama, Masafumi; Nagashima, Yoji; Kuroda, Naoto; Araki, Kimi; Eto, Masatoshi; Yao, Masahiro; Kamba, Tomomi; Suda, Toshio; Oike, Yuichi; Schmidt, Laura S.; Marston Linehan, W.

In: Molecular Cancer Research, Vol. 17, No. 8, 01.08.2019, p. 1613-1626.

Research output: Contribution to journalArticle

Baba, M, Furuya, M, Motoshima, T, Lang, M, Funasaki, S, Ma, W, Sun, HW, Hasumi, H, Huang, Y, Kato, I, Kadomatsu, T, Satou, Y, Morris, N, Karim, BO, Ileva, L, Kalen, JD, Krisna, LAW, Hasumi, Y, Sugiyama, A, Kurahashi, R, Nishimoto, K, Oyama, M, Nagashima, Y, Kuroda, N, Araki, K, Eto, M, Yao, M, Kamba, T, Suda, T, Oike, Y, Schmidt, LS & Marston Linehan, W 2019, 'TFE3 XP11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease', Molecular Cancer Research, vol. 17, no. 8, pp. 1613-1626. https://doi.org/10.1158/1541-7786.MCR-18-1235
Baba, Masaya ; Furuya, Mitsuko ; Motoshima, Takanobu ; Lang, Martin ; Funasaki, Shintaro ; Ma, Wenjuan ; Sun, Hong Wei ; Hasumi, Hisashi ; Huang, Ying ; Kato, Ikuma ; Kadomatsu, Tsuyoshi ; Satou, Yorifumi ; Morris, Nicole ; Karim, Baktiar O. ; Ileva, Lilia ; Kalen, Joseph D. ; Krisna, Luh Ade Wilan ; Hasumi, Yukiko ; Sugiyama, Aiko ; Kurahashi, Ryoma ; Nishimoto, Koshiro ; Oyama, Masafumi ; Nagashima, Yoji ; Kuroda, Naoto ; Araki, Kimi ; Eto, Masatoshi ; Yao, Masahiro ; Kamba, Tomomi ; Suda, Toshio ; Oike, Yuichi ; Schmidt, Laura S. ; Marston Linehan, W. / TFE3 XP11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease. In: Molecular Cancer Research. 2019 ; Vol. 17, No. 8. pp. 1613-1626.
@article{fd9a26012eab4c07a64c46da150639b6,
title = "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.",
author = "Masaya Baba and Mitsuko Furuya and Takanobu Motoshima and Martin Lang and Shintaro Funasaki and Wenjuan Ma and Sun, {Hong Wei} and Hisashi Hasumi and Ying Huang and Ikuma Kato and Tsuyoshi Kadomatsu and Yorifumi Satou and Nicole Morris and Karim, {Baktiar O.} and Lilia Ileva and Kalen, {Joseph D.} and Krisna, {Luh Ade Wilan} and Yukiko Hasumi and Aiko Sugiyama and Ryoma Kurahashi and Koshiro Nishimoto and Masafumi Oyama and Yoji Nagashima and Naoto Kuroda and Kimi Araki and Masatoshi Eto and Masahiro Yao and Tomomi Kamba and Toshio Suda and Yuichi Oike and Schmidt, {Laura S.} and {Marston Linehan}, W.",
year = "2019",
month = "8",
day = "1",
doi = "10.1158/1541-7786.MCR-18-1235",
language = "English",
volume = "17",
pages = "1613--1626",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85071055962&partnerID=8YFLogxK

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

VL - 17

SP - 1613

EP - 1626

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 8

ER -