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

Alessia Calcagnì,Carmine Settembre,Rossella De Cegli,Stefano Confalonieri,Eric Verschuren,Lotte Kors,Jaklien C Leemans,Salvatore Pece,Edoardo Nusco,Gabriel G Malouf,Marco Salvatore,Giovanni Bertalot,Dorien Jm Peters,Nicolina Zampelli,Emile De Heer,Andrea Ballabio,Pier Paolo Di Fiore

doi:10.7554/elife.17047

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.

Highlights

The MIT/TFE family of bHLH leucine zipper transcription factors includes the MITF, transcription factor EB (TFEB), TFE3 and TFEC genes, which are master regulators of cell homeostasis, growth and differentiationCalcagnı et al eLife 2016;5:e17047
TFEB-tRCCs are associated to a well-characterized chromosomal translocation involving the TFEB gene and the non-coding Alpha gene, generating the alpha-TFEB fusion (t (6;11) (p21.2;q13) (Davis et al, 2003; Kuiper et al, 2003)
TFEB breakpoints were in all cases observed within a 289 bp cluster region (BCR) upstream exon 3, retaining the entire TFEB coding sequence (Davis et al, 2003; Argani et al, 2005; Inamura et al, 2012)

Summary

Introduction

The MIT/TFE family of bHLH leucine zipper transcription factors includes the MITF, TFEB, TFE3 and TFEC genes, which are master regulators of cell homeostasis, growth and differentiation. Cancer Biology Human Biology and Medicine (Levy et al, 2006; Sardiello et al, 2009; Settembre et al, 2011). All family members are able to both homodimerize and heterodimerize with each other through their bHLH-LZ domain (Hemesath et al, 1994). These transcription factors bind a DNA sequence called the M-box and a non-canonical E-box sequence (TCATGTG, CATGTGA or TCATGTGA) (Hemesath et al, 1994; Aksan and Goding, 1998). A large body of evidence indicate that they play an important role in many cellular and developmental processes

Methods

Results

Conclusion