Deep multiomics profiling of brain tumors identifies signaling networks downstream of cancer driver genes.

High throughput omics approaches provide an unprecedented opportunity for dissecting molecular mechanisms in cancer biology. Here we present deep profiling of whole proteome, phosphoproteome and transcriptome in two high-grade glioma (HGG) mouse models driven by mutated RTK oncogenes, PDGFRA and NTRK1, analyzing 13,860 proteins and 30,431 phosphosites by mass spectrometry. Systems biology approaches identify numerous master regulators, including 41 kinases and 23 transcription factors.

Retinal Cell Type DNA Methylation and Histone Modifications Predict Reprogramming Efficiency and Retinogenesis in 3D Organoid Cultures.

Diverse cell types can be reprogrammed into pluripotent stem cells by ectopic expression of Oct4 (Pou5f1), Klf4, Sox3, and Myc. Many of these induced pluripotent stem cells (iPSCs) retain memory, in terms of DNA methylation and histone modifications (epigenetic memory), of their cellular origins, and this may bias subsequent differentiation. Neurons are difficult to reprogram, and there has not been a systematic side-by-side characterization of reprogramming efficiency or epigenetic memory across different neuronal subtypes.

Measuring Absolute Blood Perfusion in Mice Using Dynamic Contrast-Enhanced Ultrasound.

We investigated the feasibility of estimating absolute tissue blood perfusion using dynamic contrast-enhanced ultrasound (CEUS) imaging in mice. We developed a novel method of microbubble administration and a model-free approach to estimate absolute kidney perfusion, and explored the kidney as a reference organ to estimate absolute perfusion of a neuroblastoma tumor. We performed CEUS on the kidneys of CD1 nude mice using the VisualSonics VEVO 2100 imaging system.

The Dynamic Epigenetic Landscape of the Retina During Development, Reprogramming, and Tumorigenesis.

In the developing retina, multipotent neural progenitors undergo unidirectional differentiation in a precise spatiotemporal order. Here we profile the epigenetic and transcriptional changes that occur during retinogenesis in mice and humans. Although some progenitor genes and cell cycle genes were epigenetically silenced during retinogenesis, the most dramatic change was derepression of cell-type-specific differentiation programs.

Detection of Phenotypic Alterations Using High-Content Analysis of Whole-Slide Images.

Tumors exhibit spatial heterogeneity, as manifested in immunohistochemistry (IHC) staining patterns. Current IHC quantification methods lose information by reducing this heterogeneity in each whole-slide image (WSI) or in selective fields of view to a single staining index. The aim of this study was to investigate the sensitivity of an IHC quantification method that uses this heterogeneity to reliably compare IHC staining patterns.

Development and characterization of a human orthotopic neuroblastoma xenograft.

Neuroblastoma is a pediatric cancer of the developing sympathoadrenal lineage. The tumors are known to develop from the adrenal gland or paraspinal ganglia and have molecular and cellular features of sympathetic neurons such as dense core vesicles and catecholamine production. Here we present the detailed molecular, cellular, genetic and epigenetic characterization of an orthotopic xenograft derived from a high-risk stage 4 neuroblastoma patient.

Targeting the DNA repair pathway in Ewing sarcoma.

Ewing sarcoma (EWS) is a tumor of the bone and soft tissue that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive, but patients with metastatic or recurrent disease have a poor outcome. We found that EWS cell lines are defective in DNA break repair and are sensitive to PARP inhibitors (PARPis).