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

Author

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, and Andrea Ballabio

Subjects
renal cell carcinoma, TFEB, WNT pathway, Medicine, Science, Biology (General), QH301-705.5
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.

Published
2016
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2. Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling

Author

Stefano Confalonieri, Edoardo Nusco, Dorien J.M. Peters, Carmine Settembre, Marco Salvatore, Eric Verschuren, Andrea Ballabio, Giovanni Bertalot, Emile de Heer, Nicolina Zampelli, Gabriel G. Malouf, Alessia Calcagni, Jaklien C. Leemans, Salvatore Pece, Rossella De Cegli, Pier Paolo Di Fiore, Lotte Kors, TIGEM (Telethon Institute of Genetics and Medicine), Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM), Academical Medical Center, Leiden University Medical Center (LUMC), European Institute of Oncology [Milan] (ESMO), FIRC Institute of Molecular Oncology Foundation, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Università degli Studi di Milano [Milano] (UNIMI), Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Università degli studi di Napoli Federico II, Service d'Oncologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Universitaire de Cancérologie [Paris] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), SDN - Istituto di Ricerca Diagnostica e Nucleare, AII - Amsterdam institute for Infection and Immunity, Graduate School, Pathology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Universiteit Leiden, Università degli Studi di Milano = University of Milan (UNIMI), University of Naples Federico II = Università degli studi di Napoli Federico II, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Universitaire de Cancérologie [Sorbonne Université] (IUC), Calcagnì, Alessia, Kors, Lotte, Verschuren, Eric, DE CEGLI, Rossella, Zampelli, Nicolina, Nusco, Edoardo, Confalonieri, Stefano, Bertalot, Giovanni, Pece, Salvatore, Settembre, Carmine, Malouf, Gabriel G., Leemans, Jaklien C., de Heer, Emile, Salvatore, Marco, Peters, Dorien J. M., Di Fiore, Pier Paolo, and Ballabio, Andrea

Subjects
0301 basic medicine, Genetically modified mouse, renal cell carcinoma, Mouse, WNT pathway, Immunology and Microbiology (all), QH301-705.5, Science, Cell, TFE3, Chromosomal translocation, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Renal cell carcinoma, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biology (General), Human Biology and Medicine, Cancer Biology, TFEB, Kidney, Neuroscience (all), Biochemistry, Genetics and Molecular Biology (all), General Immunology and Microbiology, Medicine (all), General Neuroscience, Wnt signaling pathway, human biology, General Medicine, medicine.disease, 3. Good health, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Cancer research, Medicine, Research Article
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.

Published
2016
Full Text
View/download PDF

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