Orthotopic Wilms tumor xenografts derived from cell lines reflect limited aspects of tumor morphology and clinical characteristics

Mengelbier, Linda Holmquist; Bexell, Daniel; Sehic, Daniel; Ciornei, Cristina; Gisselsson, David

doi:10.1002/pbc.25131

Cited by 11 publications

(26 citation statements)

References 14 publications

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“…To elucidate the functionality of IRX3 and IRX5 in Wilms tumour development, targeted genome editing of IRX3 and IRX5 was performed on the human WiT49 Wilms tumour cell line, chosen as a model system as it retains the multi‐phasic histology of Wilms tumours when orthotopically xenografted into mice . Most importantly, the model enables the evaluation of tumour tubule formation, corresponding to Wilms tumour epithelial differentiation.…”

Section: Resultsmentioning

confidence: 99%

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

Mengelbier

Lindell-Munther

Yasui

et al. 2018

The Journal of Pathology

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Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock‐out Irx3 − /Irx5 − mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was already activated in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3 −/− cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/β‐catenin‐signalling. In contrast, IRX5 −/− cells displayed activation of Hippo and non‐canonical WNT‐signalling and generated small tumours with abundant tubulogenesis. Our findings suggest that promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Resultsmentioning

confidence: 99%

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

Mengelbier

Lindell-Munther

Yasui

et al. 2018

The Journal of Pathology

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“…Several previous studies have found that features of WT‐CLS1 were uncharacteristic of Wilms tumor without specifically identifying it as rhabdoid tumor. For example, it was previously shown that WT‐CLS1 xenografts do not recapitulate the histological and immunohistochemical characteristics of human Wilms tumor . Similarly, its gene expression pattern was unique from Wilms tumor cell lines, and it carried none of the common genomic aberrations commonly seen in Wilms tumor .…”

Section: Discussionmentioning

confidence: 99%

“…As there are a limited number of Wilms tumor cell lines available, we obtained 2 cell lines, which were previously described as Wilms tumor: WiT49 and WT‐CLS1. We overexpressed let‐7a, miR‐16, and miR‐34a in these cell lines to understand their potential as tumor suppressors in Wilms tumor.…”

Section: Introductionmentioning

confidence: 99%

WT‐CLS1 is a rhabdoid tumor cell line and can be inhibited by miR‐16

et al. 2018

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Background: Wilms tumor and rhabdoid tumor can have similar clinical presentations, but they have distinct histological and biological features. For instance, Wilms tumors commonly bear mutations in kidney differentiation or microRNA processing genes, whereas rhabdoid tumor is characterized by loss of SMARCB1. Aims:We initially set out to characterize and identify tumor suppressor microRNAs in WT-CLS1, which had been described as a Wilms tumor cell line. Methods and Results:We characterized the cell line WT-CLS1 by whole exome sequencing, RNA-seq, and xenograft histology. We measured the effect of microRNA overexpression on WiT49, WT-CLS1, BT-12, and CHLA-06-ATRT.We found that miR-16 significantly impairs cell proliferation in WT-CLS1 by repressing numerous cell cycle genes, including the D-type cyclins. In addition, we found that the WT-CLS1 cell line demonstrates the classic histological, mutational, and transcriptional hallmarks of rhabdoid tumor, including SMARCB1 loss. Lastly, miR-16 also represses cell cycle genes and impairs proliferation in the BT-12 and CHLA-06-ATRT rhabdoid tumor cell lines. Conclusions:The loss of SMARCB1 warrants reclassification of WT-CLS1 as rhabdoid tumor. Overexpression of miR-16 significantly abrogates proliferation of WT-CLS1 and other rhabdoid tumor cell lines. Further studies are necessary to gain insight into the potential for miR-16 to be a tumor suppressor or a novel therapeutic in rhabdoid tumor. KEYWORDS miR-16, rhabdoid tumor, WT-CLS1Abbreviations: ATRT, atypical teratoid/rhabdoid tumor; CDK4, cyclin-dependent kinase 4; EZH2, Enhancer of zeste homolog 2; miRNA, microRNA; SWI/SNF, Switch/ sucrose non-fermentable

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“…Several previous studies have found that features of WT-CLS1 were uncharacteristic of Wilms tumor without specifically identifying it as rhabdoid tumor. For example, it was previously shown that WT-CLS1 xenografts do not recapitulate the histological and immunohistochemical characteristics of human Wilms tumor 49 . Similarly, its gene expression pattern was unique from Wilms tumor cell lines, and it carried none of the common genomic aberrations common seen in Wilms tumor 50 .…”

Section: Discussionmentioning

confidence: 99%

miR-16 Suppresses Growth of Rhabdoid Tumor Cells

Stroup

Yeu

Budhipramono

et al. 2017

Preprint

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BackgroundRhabdoid tumor is a highly aggressive pediatric cancer characterized by biallelic loss and/or mutation of SMARCB1. Outcomes remain poor, and there are no established ways to target the tumorigenic pathways driven by SMARCB1 inactivation. SMARCB1 loss leads to an increase in cyclin D transcription.ProcedureWe characterized the cell line WT-CLS1, which has been described previously as Wilms tumor, by whole-exome sequencing, RNA-seq, and xenograft histology. We measured the effect of microRNA overexpression on WT-CLS1, BT-12, and CHLA-06-ATRT.ResultsWe found that WT-CLS1 demonstrates the histological, mutational, and transcriptional hallmarks of rhabdoid tumor. Because the microRNAs let-7 and miR-16 can target cyclin D genes, we next overexpressed each of these microRNAs in WT-CLS1. We found that miR-16 reduced cell accumulation. This was accompanied by a decrease in proliferation markers and an increase in apoptosis markers. These results were replicated in the BT-12 and CHLA-06-ATRT cell lines.ConclusionsThe loss-of-function SMARCB1 mutation found in WT-CLS1, in conjunction with immunohistochemical and gene expression analysis, warrants reclassification of this cell line as rhabdoid tumor. Proliferation of WT-CLS1 and other rhabdoid tumor cell lines is significantly abrogated by miR-16 overexpression. Further studies are necessary to gain insight into the potential for miR-16 to be used as a novel therapeutic in rhabdoid tumor.Abbreviations(ATRT)atypical teratoid/rhabdoid tumor(miRNA)microRNA(dox)doxycycline(OD595)optical density at 595 nm(CDK4)cyclin-dependent kinase 4

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Orthotopic Wilms tumor xenografts derived from cell lines reflect limited aspects of tumor morphology and clinical characteristics

Abstract: From the three tested cell lines, orthotopic WiT49 xenografts best reflect the triphasic pattern of classical WT.

Cited by 11 publications

References 14 publications

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

WT‐CLS1 is a rhabdoid tumor cell line and can be inhibited by miR‐16

miR-16 Suppresses Growth of Rhabdoid Tumor Cells

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