Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling

Alessia Calcagnì, Lotte Kors, Eric Verschuren, Rossella De Cegli, Nicolina Zampelli, Edoardo Nusco, Stefano Confalonieri, Giovanni Bertalot, Salvatore Pece, Carmine Settembre, G. Malouf, Jaklien C. Leemans, Emile de Heer, Marco Salvatore, Dorien Peters, Pier Paolo Di Fiore, Andrea Ballabio

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Abstract

TFE-fusion renal cell carcinomas (TFE-fusion RCCs) are caused by chromosomal translocations that lead to overexpression of the TFEB and TFE3 genes (Kauffman et al., 2014). The mechanisms leading to kidney tumor development remain uncharacterized and effective therapies are yet to be identified. Hence, the need to model these diseases in an experimental animal system (Kauffman et al., 2014). Here, we show that kidney-specific TFEB overexpression in transgenic mice, resulted in renal clear cells, multi-layered basement membranes, severe cystic pathology, and ultimately papillary carcinomas with hepatic metastases. These features closely recapitulate those observed in both TFEB- and TFE3-mediated human kidney tumors. Analysis of kidney samples revealed transcriptional induction and enhanced signaling of the WNT b-catenin pathway. WNT signaling inhibitors normalized the proliferation rate of primary kidney cells and significantly rescued the disease phenotype in vivo. These data shed new light on the mechanisms underlying TFE-fusion RCCs and suggest a possible therapeutic strategy based on the inhibition of the WNT pathway.

Original languageEnglish
Article numbere17047
JournaleLife
Volume5
Issue numberSeptember
DOIs
Publication statusPublished - Sep 26 2016

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Calcagnì, A., Kors, L., Verschuren, E., De Cegli, R., Zampelli, N., Nusco, E., Confalonieri, S., Bertalot, G., Pece, S., Settembre, C., Malouf, G., Leemans, J. C., de Heer, E., Salvatore, M., Peters, D., Di Fiore, P. P., & Ballabio, A. (2016). Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling. eLife, 5(September), [e17047]. https://doi.org/10.7554/eLife.17047