Forty-five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor

Abstract

The lack of model systems has limited the preclinical discovery and testing of therapies for Wilms tumor (WT) patients who have poor outcomes. Herein, we establish 45 heterotopic WT patient-derived xenografts (WTPDX) in CB17 scid-/- mice that capture the biological heterogeneity of Wilms tumor (WT). Among these 45 total WTPDX, 6 from patients with diffuse anaplastic tumors, 9 from patients who experienced disease relapse, and 13 from patients with bilateral disease are included. Early passage WTPDX show evidence of clonal selection, clonal evolution and enrichment of blastemal gene expression. Favorable histology WTPDX are sensitive, whereas unfavorable histology WTPDX are resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test targeted therapies for WT patient groups with poor outcomes.

Xenograft models for pediatric cancer therapies

“…Finally, another group generated a WT PDX library, successfully xenografting 45 WT patient samples into SCID mice. These PDXs demonstrated consistent enrichment of the blastema relative to primary tumors 136 . This PDX library was treated with doxorubicin, actinomycin D, and vincristine, demonstrating sensitivity in xenografts derived from favorable histology WT, and more frequent refractoriness in PDXs from anaplastic WT samples 136 .…”

“…These PDXs demonstrated consistent enrichment of the blastema relative to primary tumors 136 . This PDX library was treated with doxorubicin, actinomycin D, and vincristine, demonstrating sensitivity in xenografts derived from favorable histology WT, and more frequent refractoriness in PDXs from anaplastic WT samples 136 . WT models have also been used to test novel therapies, including a human NCAM antibody–drug conjugate called lorvotuzumab–mertansine.…”

Targeting TRIP13 in Wilms Tumor with Nuclear Export Inhibitors

“…Next, we created a two-dimensional map of the tumor and cell line transcriptomes using the uniform manifold approximation and projection (UMAP) 27 and compared it to TARGET 28 and St. Jude Children’s Research Hospital’s WT datasets 19 ( Methods ). We observed that our WT cell lines clustered closely with the WT tumor samples ( Fig 1b) .…”

MethylationToActivity: a deep-learning framework that reveals promoter activity landscapes from DNA methylomes in individual tumors

“…Despite the documented epigenetic heterogeneity [ 48 ], a common practice in deciphering major HM deregulations in various cancers is to extrapolate the epigenetic profiles from related cancer models (surrogate models). Many studies [ 43 , 44 , 49 – 52 ] have compared model systems to primary tumors with respect to characteristics such as mutations, gene expression, and DNAm signatures. In this study, we began by evaluating the level of promoter activity diversity in closely related NBL models.…”