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

Authors :
Alessia Calcagnì
Lotte kors
Eric Verschuren
Rossella De Cegli
Nicolina Zampelli
Edoardo Nusco
Stefano Confalonieri
Giovanni Bertalot
Salvatore Pece
Carmine Settembre
Gabriel G Malouf
Jaklien C Leemans
Emile de Heer
Marco Salvatore
Dorien JM Peters
Pier Paolo Di Fiore
Andrea Ballabio
Source :
eLife, Vol 5 (2016)
Publication Year :
2016
Publisher :
eLife Sciences Publications Ltd, 2016.

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 β-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.

Details

Language :
English
ISSN :
2050084X
Volume :
5
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.32edca15298541028482d193be8401b5
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.17047