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Elife. 2016 Sep 26;5. pii: e17047. doi: 10.7554/eLife.17047.

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

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Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples, Italy.
Department of Pathology, Academical Medical Center, Amsterdam, The Netherlands.
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
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.
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.
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.
IRCCS-SDN, Naples, Italy.


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.


TFEB; WNT pathway; cancer biology; human biology; medicine; mouse; renal cell carcinoma

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