PD-L1 expression is mediated by microRNA processing, Wnt/β-catenin signaling, and chemotherapy in Wilms tumor.

Inhibition of immune checkpoint proteins is effective in adult cancers but has shown limited efficacy in pediatric cancers. While factors regulating expression of immune checkpoint proteins such as PD-L1 are well-documented in adult cancers, their regulation is poorly understood in pediatric cancers. Here, we show that PD-L1 is upregulated in distinct subsets of Wilms tumor, the most common pediatric kidney cancer.

Actinomycin D and bortezomib disrupt protein homeostasis in Wilms tumor.

Wilms tumor is the most common kidney cancer in children, and diffusely anaplastic Wilms tumor is the most chemoresistant histological subtype. Here we explore how Wilms tumor cells evade the common chemotherapeutic drug actinomycin D, which inhibits ribosomal RNA biogenesis. Using ribosome profiling, protein arrays, and a genome-wide knockout screen, we describe how actinomycin D disrupts protein homeostasis and blocks cell cycle progression.

DROSHA Regulates Mesenchymal Gene Expression in Wilms Tumor.

Wilms tumor, the most common pediatric kidney cancer, resembles embryonic renal progenitors. Currently, there are no ways to therapeutically target Wilms tumor driver mutations, such as in the microRNA processing gene DROSHA. In this study, we used a "multiomics" approach to define the effects of DROSHA mutation in Wilms tumor.

The neural stem-cell marker CD24 is specifically upregulated in IDH-mutant glioma.

Background: Malignant gliomas have disproportionally high morbidity and mortality. Heterozygous mutations in the isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, resulting in predominantly arginine to histidine substitution at codon 132. Because IDH1 requires a wild-type allele to produce (D)-2-hydroxyglutarate for epigenetic reprogramming, loss of IDH1 heterozygosity is associated with glioma progression in an IDH1-wildtype-like phenotype.

Extracellular glutamate and IDH1 inhibitor promote glioma growth by boosting redox potential.

Purpose: Somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, mostly substituting Arg132 with histidine, are associated with better patient survival, but glioma recurrence and progression are nearly inevitable, resulting in disproportionate morbidity and mortality. Our previous studies demonstrated that in contrast to hemizygous IDH1 (loss of wild-type allele), heterozygous IDH1 is intrinsically glioma suppressive but its suppression of three-dimensional (3D) growth is negated by extracellular glutamate and reducing equivalent. This study sought to understand the importance of 3D culture in IDH1 biology and the underlying mechanism of the glutamate effect.

IDH1 is intrinsically tumor-suppressive but functionally attenuated by the glutamate-rich cerebral environment.

Recurrent heterozygous mutation of isocitrate dehydrogenase 1 gene (), predominantly resulting in histidine substitution at arginine 132, was first identified in glioma. The biological significance of IDH1, however, has been controversial, and its prevalent association with glioma remains enigmatic. Although recent studies indicate that IDH1 is nonessential to tumor growth or even anti-tumor growth, whether IDH1 initiates gliomagenesis remains obscure.

In Vivo Manipulation of HIF-1α Expression During Glioma Genesis.

Hypoxia has long been recognized as a driving force of tumor progression and therapeutic resistance, and the transcription factor HIF-1α is believed to play a crucial role in these processes. Here we describe an efficient RCAS/Nes-TVA system that allows for in vivo manipulation of HIF-1α expression in the mouse neural progenitor cells. Simple production of the recombinant avian virus RCAS enables quick delivery of gene of interest through injection into the neural progenitors of transgenic mice expressing the viral cognate receptor TVA under the nestin promoter.

Functional requirement of a wild-type allele for mutant IDH1 to suppress anchorage-independent growth through redox homeostasis.

Mutations of isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, arguably preceding all known genetic alterations during tumor development. IDH1 mutations nearly invariably target the enzymatic active site Arg132, giving rise to the predominant IDH1. Cells harboring IDH1 -heterozygous mutation produce 2-hydroxyglutarate (2-HG), which results in histone and DNA hypermethylation.