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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

Kidney-specific Tfeb overexpression is associated with cancer development in Cdh16Cre::Tfebfs and Cdh16CreErt2::Tfebfs mice.(A) 18F-FDG PET/CT scan on P30 Cdh16Cre::Tfebfs mice. (B) HE and Ki67 staining performed on Cdh16Cre::Tfebfs mice at P1, P12, P30 and 5 months. Beginning at P12 the increase in cyst size is associated with an increase in papillary proliferation that becomes completely neoplastic by 5 months. NP, Neoplastic Papillae. (C–H) Representative images of neoplastic lesions at different stages: (C) neoplastic nodules (arrows) in P12 Cdh16Cre::Tfebfs mice; (D) micropapillae (arrows) and (E) hobnail-like cells (arrows) in P30 Cdh16Cre::Tfebfs mice; (F) mitotic spindles (arrows) in 5-month-old Cdh16Cre::Tfebfs mice; (G) microcalcifications (asterisk) in tam-treated Cdh16CreErt2::Tfebfs mice induced at P14 and sacrificed at 5 months; (H) neoplastic nests (NN) and clear cells (CCs) in tam-treated Cdh16CreErt2::Tfebfs mice induced at P12 and sacrificed at P90. (I) HE staining of neoplastic lesions invading the surrounding stroma (arrows) in Cdh16Cre::Tfebfs and in tam-treated Cdh16CreErt2::Tfebfs mice. (L) Liver metastases in 5 month-old Cdh16Cre::Tfebfs mice stained for HE, Ki67, PAX8 and CK7.DOI:http://dx.doi.org/10.7554/eLife.17047.006
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fig2: Kidney-specific Tfeb overexpression is associated with cancer development in Cdh16Cre::Tfebfs and Cdh16CreErt2::Tfebfs mice.(A) 18F-FDG PET/CT scan on P30 Cdh16Cre::Tfebfs mice. (B) HE and Ki67 staining performed on Cdh16Cre::Tfebfs mice at P1, P12, P30 and 5 months. Beginning at P12 the increase in cyst size is associated with an increase in papillary proliferation that becomes completely neoplastic by 5 months. NP, Neoplastic Papillae. (C–H) Representative images of neoplastic lesions at different stages: (C) neoplastic nodules (arrows) in P12 Cdh16Cre::Tfebfs mice; (D) micropapillae (arrows) and (E) hobnail-like cells (arrows) in P30 Cdh16Cre::Tfebfs mice; (F) mitotic spindles (arrows) in 5-month-old Cdh16Cre::Tfebfs mice; (G) microcalcifications (asterisk) in tam-treated Cdh16CreErt2::Tfebfs mice induced at P14 and sacrificed at 5 months; (H) neoplastic nests (NN) and clear cells (CCs) in tam-treated Cdh16CreErt2::Tfebfs mice induced at P12 and sacrificed at P90. (I) HE staining of neoplastic lesions invading the surrounding stroma (arrows) in Cdh16Cre::Tfebfs and in tam-treated Cdh16CreErt2::Tfebfs mice. (L) Liver metastases in 5 month-old Cdh16Cre::Tfebfs mice stained for HE, Ki67, PAX8 and CK7.DOI:http://dx.doi.org/10.7554/eLife.17047.006

Mentions: 18F-FDG PET analysis showed a higher glucose consumption in the kidneys of transgenic animals compared to controls, indicating a higher rate of glucose metabolism and suggesting a neoplastic transformation (Figure 2A). Similarly with PET analysis, HE and Ki67 stainings of the kidneys of Cdh16Cre::Tfebfs mice revealed progressive hyperproliferation, which evolved into Ki67-positive neoplastic papillae at 5 months (Figure 2B). Neoplastic nodules, micropapillae and Hobnail-like cells, and mitotic spindles were detected at P12, 1 month, and 5 months, respectively (Figure 2C–F). Focal microcalcifications (Figure 2G), together with Clear Cells, and nests of neoplastic cells (Figure 2H) were also detected in Cdh16CreErt2::Tfebfs mice.10.7554/eLife.17047.006Figure 2.Kidney-specific Tfeb overexpression is associated with cancer development in Cdh16Cre::Tfebfs and Cdh16CreErt2::Tfebfs mice.


Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling
Kidney-specific Tfeb overexpression is associated with cancer development in Cdh16Cre::Tfebfs and Cdh16CreErt2::Tfebfs mice.(A) 18F-FDG PET/CT scan on P30 Cdh16Cre::Tfebfs mice. (B) HE and Ki67 staining performed on Cdh16Cre::Tfebfs mice at P1, P12, P30 and 5 months. Beginning at P12 the increase in cyst size is associated with an increase in papillary proliferation that becomes completely neoplastic by 5 months. NP, Neoplastic Papillae. (C–H) Representative images of neoplastic lesions at different stages: (C) neoplastic nodules (arrows) in P12 Cdh16Cre::Tfebfs mice; (D) micropapillae (arrows) and (E) hobnail-like cells (arrows) in P30 Cdh16Cre::Tfebfs mice; (F) mitotic spindles (arrows) in 5-month-old Cdh16Cre::Tfebfs mice; (G) microcalcifications (asterisk) in tam-treated Cdh16CreErt2::Tfebfs mice induced at P14 and sacrificed at 5 months; (H) neoplastic nests (NN) and clear cells (CCs) in tam-treated Cdh16CreErt2::Tfebfs mice induced at P12 and sacrificed at P90. (I) HE staining of neoplastic lesions invading the surrounding stroma (arrows) in Cdh16Cre::Tfebfs and in tam-treated Cdh16CreErt2::Tfebfs mice. (L) Liver metastases in 5 month-old Cdh16Cre::Tfebfs mice stained for HE, Ki67, PAX8 and CK7.DOI:http://dx.doi.org/10.7554/eLife.17047.006
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Related In: Results  -  Collection

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fig2: Kidney-specific Tfeb overexpression is associated with cancer development in Cdh16Cre::Tfebfs and Cdh16CreErt2::Tfebfs mice.(A) 18F-FDG PET/CT scan on P30 Cdh16Cre::Tfebfs mice. (B) HE and Ki67 staining performed on Cdh16Cre::Tfebfs mice at P1, P12, P30 and 5 months. Beginning at P12 the increase in cyst size is associated with an increase in papillary proliferation that becomes completely neoplastic by 5 months. NP, Neoplastic Papillae. (C–H) Representative images of neoplastic lesions at different stages: (C) neoplastic nodules (arrows) in P12 Cdh16Cre::Tfebfs mice; (D) micropapillae (arrows) and (E) hobnail-like cells (arrows) in P30 Cdh16Cre::Tfebfs mice; (F) mitotic spindles (arrows) in 5-month-old Cdh16Cre::Tfebfs mice; (G) microcalcifications (asterisk) in tam-treated Cdh16CreErt2::Tfebfs mice induced at P14 and sacrificed at 5 months; (H) neoplastic nests (NN) and clear cells (CCs) in tam-treated Cdh16CreErt2::Tfebfs mice induced at P12 and sacrificed at P90. (I) HE staining of neoplastic lesions invading the surrounding stroma (arrows) in Cdh16Cre::Tfebfs and in tam-treated Cdh16CreErt2::Tfebfs mice. (L) Liver metastases in 5 month-old Cdh16Cre::Tfebfs mice stained for HE, Ki67, PAX8 and CK7.DOI:http://dx.doi.org/10.7554/eLife.17047.006
Mentions: 18F-FDG PET analysis showed a higher glucose consumption in the kidneys of transgenic animals compared to controls, indicating a higher rate of glucose metabolism and suggesting a neoplastic transformation (Figure 2A). Similarly with PET analysis, HE and Ki67 stainings of the kidneys of Cdh16Cre::Tfebfs mice revealed progressive hyperproliferation, which evolved into Ki67-positive neoplastic papillae at 5 months (Figure 2B). Neoplastic nodules, micropapillae and Hobnail-like cells, and mitotic spindles were detected at P12, 1 month, and 5 months, respectively (Figure 2C–F). Focal microcalcifications (Figure 2G), together with Clear Cells, and nests of neoplastic cells (Figure 2H) were also detected in Cdh16CreErt2::Tfebfs mice.10.7554/eLife.17047.006Figure 2.Kidney-specific Tfeb overexpression is associated with cancer development in Cdh16Cre::Tfebfs and Cdh16CreErt2::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 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