Analysis of TFEB function in Ksp-Cadherin16 CRE mouse lines to model a particular type of renal cell carcinoma

TFE-fusion renal cell carcinomas (TFE-fusion RCCs) are caused by chromosomal translocations that lead to the overexpression of the TFE3 and TFEB genes Kauffman et al, 2014). The mechanisms causing kidney tumour development starting from TFE3/TFEB gene overexpression, remain largely uncharacterized and effective targeted 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 both constitutive and inducible conditional transgenic mouse lines, resulted in a phenotype characterized by renal clear cells, multi-layered basement membranes, severe cystic pathology, and ultimately papillary carcinomas with hepatic metastases. These features closely recapitulate the phenotype observed in both TFEB- and TFE3-mediated human kidney tumors. Analysis of kidney samples from these mice revealed both transcriptional induction of genes belonging to the WNT pathway and enhanced WNT βcatenin signalling. The use of specific WNT signalling inhibitors normalized the proliferation rate of primary kidney cells derived from transgenic mice and significantly rescued the disease phenotype in the mouse model. 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