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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

In vivo treatment of Cdh16Cre::Tfebfs mice with the WNT inhibitor PKF118-310 partially rescues cystic and neoplastic phenotypes.Measurements of different parameters related to the cystic and papillary phenotype on six animals treated with vehicle (DMSO) and six animals treated with drug (PKF118-310). Values are shown as means (± SEM) when appropriate and are represented separately for each animal.DOI:http://dx.doi.org/10.7554/eLife.17047.019
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fig6s1: In vivo treatment of Cdh16Cre::Tfebfs mice with the WNT inhibitor PKF118-310 partially rescues cystic and neoplastic phenotypes.Measurements of different parameters related to the cystic and papillary phenotype on six animals treated with vehicle (DMSO) and six animals treated with drug (PKF118-310). Values are shown as means (± SEM) when appropriate and are represented separately for each animal.DOI:http://dx.doi.org/10.7554/eLife.17047.019

Mentions: Based on the results obtained in primary kidney cells, we tested whether WNT inhibition could ameliorate the disease phenotype in vivo. P21 Cdh16Cre::Tfebfs transgenic animals were treated with daily IP injections of PKF118-310 for 30 days. At the end of the treatment, they showed an almost complete rescue of both cystic and cancer phenotypes (Figure 6A). Indeed, treated animals showed nearly normal KW/BW ratios (Figure 6B) and a significant reduction of many parameters of cystic and neoplastic pathology, such as the number and size of cysts and neoplastic papillae, and levels of Ki67 (Figure 6C and D, Figure 6—figure supplement 1, Figure 6—source data 1). We confirmed that drug-treatment in Cdh16Cre::Tfebfs mice suppressed the WNT pathway both at the mRNA and protein levels, as shown by the reduction of the mRNA levels of the WNT direct gene targets Cyclin D1, Myc and Axin2 (Figure 6—figure supplement 2A), by the reduction of Cyclin D1 and MYC proteins (Figure 6—figure supplement 2B) and by the decrease of Cyclin D1-positive nuclei in Cdh16Cre::Tfebfs drug-treated mice (Figure 6—figure supplement 2C). Furthermore, WNT inhibition resulted in normalization of expression levels of the gene encoding the transmembrane Glycoprotein nmb (Gpnmb) (Figure 6E and F), a known marker of melanomas, gliomas and breast cancers, which is also overexpressed in TFE-fusion ccRCCs (Malouf et al., 2014; Zhou et al., 2012). Interestingly, this gene is a direct target of TFEB, based on promoter (Table 3) and ChiP-Seq analysis (Sardiello et al., 2009) (Table 4).10.7554/eLife.17047.017Figure 6.Treatment with WNT inhibitor attenuates cystic and neoplastic phenotypes.


Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling
In vivo treatment of Cdh16Cre::Tfebfs mice with the WNT inhibitor PKF118-310 partially rescues cystic and neoplastic phenotypes.Measurements of different parameters related to the cystic and papillary phenotype on six animals treated with vehicle (DMSO) and six animals treated with drug (PKF118-310). Values are shown as means (± SEM) when appropriate and are represented separately for each animal.DOI:http://dx.doi.org/10.7554/eLife.17047.019
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Related In: Results  -  Collection

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fig6s1: In vivo treatment of Cdh16Cre::Tfebfs mice with the WNT inhibitor PKF118-310 partially rescues cystic and neoplastic phenotypes.Measurements of different parameters related to the cystic and papillary phenotype on six animals treated with vehicle (DMSO) and six animals treated with drug (PKF118-310). Values are shown as means (± SEM) when appropriate and are represented separately for each animal.DOI:http://dx.doi.org/10.7554/eLife.17047.019
Mentions: Based on the results obtained in primary kidney cells, we tested whether WNT inhibition could ameliorate the disease phenotype in vivo. P21 Cdh16Cre::Tfebfs transgenic animals were treated with daily IP injections of PKF118-310 for 30 days. At the end of the treatment, they showed an almost complete rescue of both cystic and cancer phenotypes (Figure 6A). Indeed, treated animals showed nearly normal KW/BW ratios (Figure 6B) and a significant reduction of many parameters of cystic and neoplastic pathology, such as the number and size of cysts and neoplastic papillae, and levels of Ki67 (Figure 6C and D, Figure 6—figure supplement 1, Figure 6—source data 1). We confirmed that drug-treatment in Cdh16Cre::Tfebfs mice suppressed the WNT pathway both at the mRNA and protein levels, as shown by the reduction of the mRNA levels of the WNT direct gene targets Cyclin D1, Myc and Axin2 (Figure 6—figure supplement 2A), by the reduction of Cyclin D1 and MYC proteins (Figure 6—figure supplement 2B) and by the decrease of Cyclin D1-positive nuclei in Cdh16Cre::Tfebfs drug-treated mice (Figure 6—figure supplement 2C). Furthermore, WNT inhibition resulted in normalization of expression levels of the gene encoding the transmembrane Glycoprotein nmb (Gpnmb) (Figure 6E and F), a known marker of melanomas, gliomas and breast cancers, which is also overexpressed in TFE-fusion ccRCCs (Malouf et al., 2014; Zhou et al., 2012). Interestingly, this gene is a direct target of TFEB, based on promoter (Table 3) and ChiP-Seq analysis (Sardiello et al., 2009) (Table 4).10.7554/eLife.17047.017Figure 6.Treatment with WNT inhibitor attenuates cystic and neoplastic phenotypes.

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