Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling.
TFE-fusion renal cell carcinomas (TFE-fusionRCCs) are caused by chromosomal translocations that lead to overexpression of theTFEBandTFE3genes (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-specificTFEBoverexpression 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 bothTFEB-andTFE3-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 underlyingTFE-fusionRCCsand suggest a possible therapeutic strategy based on the inhibition of the WNT pathway.
Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples, Italy.
Alessia
A
Calcagnì
Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples, Italy.|Department of Pathology, Academical Medical Center, Amsterdam, The Netherlands.
Lotte
L
Kors
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
Eric
E
Verschuren
Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples, Italy.
Rossella
R
De Cegli
Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples, Italy.
Nicolina
N
Zampelli
Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples, Italy.
Edoardo
E
Nusco
Molecular Medicine Program, European Institute of Oncology, Milan, Italy.|IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.
Stefano
S
Confalonieri
Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
Giovanni
G
Bertalot
Molecular Medicine Program, European Institute of Oncology, Milan, Italy.|Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Salvatore
S
Pece
Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples, Italy.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, United States.|Medical Genetics, Federico II University, Naples, Italy.|Medical Genetics, Department of Medical and Translational Sciences, Federico II University, Naples, Italy.
Carmine
C
Settembre
Department of Medical Oncology Groupe Hospitalier Pitie-Salpetriere, University Paris 6, Paris, France.|Assistance Publique Hopitaux de Paris, University Paris 6, Paris, France.|Faculty of Medicine Pierre et Marie Curie, University Paris 6, Paris, France.|Institut Universitaire de Cancerologie GRC5, University Paris 6, Paris, France.
Gabriel G
GG
Malouf
Department of Pathology, Academical Medical Center, Amsterdam, The Netherlands.
Jaklien C
JC
Leemans
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Emile
E
de Heer
IRCCS-SDN, Naples, Italy.
Marco
M
Salvatore
Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
Dorien Jm
DJ
Peters
Molecular Medicine Program, European Institute of Oncology, Milan, Italy.|IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.|Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Pier Paolo
PP
Di Fiore
Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples, Italy.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, United States.|Medical Genetics, Federico II University, Naples, Italy.|Medical Genetics, Department of Medical and Translational Sciences, Federico II University, Naples, Italy.
Andrea
http://orcid.org/0000-0003-1381-4604
A
Ballabio
TFEB; WNT pathway; cancer biology; human biology; medicine; mouse; renal cell carcinoma
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