TY - JOUR
T1 - Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling
AU - Calcagnì, Alessia
AU - Kors, Lotte
AU - Verschuren, Eric
AU - De Cegli, Rossella
AU - Zampelli, Nicolina
AU - Nusco, Edoardo
AU - Confalonieri, Stefano
AU - Bertalot, Giovanni
AU - Pece, Salvatore
AU - Settembre, Carmine
AU - Malouf, G.
AU - Leemans, Jaklien C.
AU - de Heer, Emile
AU - Salvatore, Marco
AU - Peters, Dorien
AU - Di Fiore, Pier Paolo
AU - Ballabio, Andrea
PY - 2016/9/26
Y1 - 2016/9/26
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.17047
DO - 10.7554/eLife.17047
M3 - Article
VL - 5
JO - eLife
JF - eLife
SN - 2050-084X
IS - September
M1 - e17047
ER -