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

View Article: PubMed Central - PubMed

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.

Doi:: http://dx.doi.org/10.7554/eLife.17047.001

No MeSH data available.


Related in: MedlinePlus

ErbB and WNT transcriptional profiles in Cdh16CreErt2::Tfebfs mice.Transcriptional analyses performed on Cdh16CreErt2::Tfebfs mice. (A,B) mRNA levels of previously validated genes belonging to the WNT (left graphs) and ErbB (right graphs) signaling pathways assessed in P90 Cdh16CreErt2::Tfebfs mice induced at (A) P14 and at (B) P30 with tamoxifen respectively. Data are shown as the average (± SEM) of at least Cdh16CreErt2::Tfebfs mice and values are normalized to the wild-type line. (*p<0.05, **p<0.01, ***p<0.001, two-sided Student’s t test).DOI:http://dx.doi.org/10.7554/eLife.17047.010
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fig3s1: ErbB and WNT transcriptional profiles in Cdh16CreErt2::Tfebfs mice.Transcriptional analyses performed on Cdh16CreErt2::Tfebfs mice. (A,B) mRNA levels of previously validated genes belonging to the WNT (left graphs) and ErbB (right graphs) signaling pathways assessed in P90 Cdh16CreErt2::Tfebfs mice induced at (A) P14 and at (B) P30 with tamoxifen respectively. Data are shown as the average (± SEM) of at least Cdh16CreErt2::Tfebfs mice and values are normalized to the wild-type line. (*p<0.05, **p<0.01, ***p<0.001, two-sided Student’s t test).DOI:http://dx.doi.org/10.7554/eLife.17047.010

Mentions: To characterize the molecular mechanisms and identify the relevant pathways leading from TFEB overexpression to tumor development, we performed transcriptome analysis on kidney samples from Cdh16Cre::Tfebfs and Cdh16Cremice at P0 (GSE62977-KSP_P0 dataset) and at P14 (GSE63376-KSP_P14 dataset) (see Materials and methods) and found that Tfeb overexpression perturbed the kidney transcriptome in a statistically significant manner (Figure 3—source data 1 and 2, see also Materials and methods). Targeted analysis of the transcriptomic data revealed a significant induction of genes belonging to both ErbB and WNT signaling pathways. This was confirmed by real-time PCR performed on Cdh16Cre::Tfebfs mice at several developmental stages. Moreover, real-time PCR revealed an induction of Myc and Axin2 genes, which are, together with Ccnd1, well-established WNT direct gene targets (Clevers, 2006) (Figure 3A and B, Tables 1 and 2). Kidneys from Cdh16CreErt2::Tfebfs mice also had higher levels of all WNT-related genes that were identified in the constitutive line, and of many of the ErbB-related genes (Figure 3—figure supplement 1A and B).10.7554/eLife.17047.007Figure 3.Activation of ErbB and WNT signaling pathways in kidneys from Cdh16Cre::Tfebfs mice.


Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling
ErbB and WNT transcriptional profiles in Cdh16CreErt2::Tfebfs mice.Transcriptional analyses performed on Cdh16CreErt2::Tfebfs mice. (A,B) mRNA levels of previously validated genes belonging to the WNT (left graphs) and ErbB (right graphs) signaling pathways assessed in P90 Cdh16CreErt2::Tfebfs mice induced at (A) P14 and at (B) P30 with tamoxifen respectively. Data are shown as the average (± SEM) of at least Cdh16CreErt2::Tfebfs mice and values are normalized to the wild-type line. (*p<0.05, **p<0.01, ***p<0.001, two-sided Student’s t test).DOI:http://dx.doi.org/10.7554/eLife.17047.010
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fig3s1: ErbB and WNT transcriptional profiles in Cdh16CreErt2::Tfebfs mice.Transcriptional analyses performed on Cdh16CreErt2::Tfebfs mice. (A,B) mRNA levels of previously validated genes belonging to the WNT (left graphs) and ErbB (right graphs) signaling pathways assessed in P90 Cdh16CreErt2::Tfebfs mice induced at (A) P14 and at (B) P30 with tamoxifen respectively. Data are shown as the average (± SEM) of at least Cdh16CreErt2::Tfebfs mice and values are normalized to the wild-type line. (*p<0.05, **p<0.01, ***p<0.001, two-sided Student’s t test).DOI:http://dx.doi.org/10.7554/eLife.17047.010
Mentions: To characterize the molecular mechanisms and identify the relevant pathways leading from TFEB overexpression to tumor development, we performed transcriptome analysis on kidney samples from Cdh16Cre::Tfebfs and Cdh16Cremice at P0 (GSE62977-KSP_P0 dataset) and at P14 (GSE63376-KSP_P14 dataset) (see Materials and methods) and found that Tfeb overexpression perturbed the kidney transcriptome in a statistically significant manner (Figure 3—source data 1 and 2, see also Materials and methods). Targeted analysis of the transcriptomic data revealed a significant induction of genes belonging to both ErbB and WNT signaling pathways. This was confirmed by real-time PCR performed on Cdh16Cre::Tfebfs mice at several developmental stages. Moreover, real-time PCR revealed an induction of Myc and Axin2 genes, which are, together with Ccnd1, well-established WNT direct gene targets (Clevers, 2006) (Figure 3A and B, Tables 1 and 2). Kidneys from Cdh16CreErt2::Tfebfs mice also had higher levels of all WNT-related genes that were identified in the constitutive line, and of many of the ErbB-related genes (Figure 3—figure supplement 1A and B).10.7554/eLife.17047.007Figure 3.Activation of ErbB and WNT signaling pathways in kidneys from Cdh16Cre::Tfebfs mice.

View Article: PubMed Central - PubMed

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 &beta;-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.

Doi:: http://dx.doi.org/10.7554/eLife.17047.001

No MeSH data available.


Related in: MedlinePlus