Biology subjects

Nuechterlein, N.

Publications and source records attributed to Nuechterlein, N..

5 recordsLinked to original sources

bioRxiv2026

Lactate epigenetically shapes tumor cell states in H3K27M diffuse midline gliomas

H3K27M diffuse midline gliomas (DMGs) are lethal and lack treatment options. These tumors exhibit tumor heterogeneity with aggressive oligodendrocyte precursor (OPC)- and mesenchymal (MES)-like cell states. Because all tumor cells bear H3K27M, tumor heterogeneity has been attributed to microenvironmental cues that remain obscure. H3K27M DMGs exhibit increased glycolysis and the Warburg effect to produce lactate. Lactate can directly modify histone lysines including H3K27Lac, and we hypothesized that lactate epigenetically regulates tumor cell states in H3K27M DMGs. We undertook a comprehensive and integrated analysis of H3K27M DMG cell lines, animal models, tumor tissues, and magnetic resonance spectroscopy in patients to decipher the epigenetic roles of lactate. Here, we report that H3K27M cells uniquely exhibit elevation of the activating mark H3K27Lac. We observed significant heterogeneity in lactate levels within tumors, and the addition of exogenous lactate resulted in marked increases in H3K27Lac and the expression of critical OPC- and MES- like gene signature genes, which correlates with poorer patient outcomes. Our therapeutic approach leverages the inhibition of CBP/p300, which deposits both H3K27Lac and H3K27ac. Targeting CBP/p300 effectively reduces both H3K27Lac and H3K27ac levels, suppresses key OPC- and MES-like signatures, and shows efficacy in preclinical models. Collectively, our findings identify lactate as a key player in the epigenetic regulation of tumor cell state heterogeneity and suggest that targeting this pathway offers promise for addressing the heterogeneous complexities of H3K27M DMGs.

molecular biology↗

bioRxiv2024

Transcriptomic landscape identifies two unrecognized ependymoma subtypes and novel pathways in medulloblastoma

Medulloblastoma and ependymoma are common pediatric central nervous system tumors with significant molecular and clinical heterogeneity. We collected bulk RNA sequencing data from 888 medulloblastoma and 370 ependymoma tumors to establish a comprehensive reference landscape. Following rigorous batch effect correction, normalization, and dimensionality reduction, we constructed a unified landscape to explore gene expression, signaling pathways, RNA fusions, and copy number variations. Our analysis revealed distinct clustering patterns, including two primary ependymoma compartments, EPN-E1 and EPN-E2, each with specific RNA fusions and molecular signatures. In medulloblastoma, we observed precise stratification of Group 3/4 tumors by subtype and in SHH tumors by patient age. This landscape serves as a vital resource for identifying biomarkers, refining diagnoses, and enables the mapping of new patients bulk RNA-seq data onto the reference framework to predict biology and outcome from nearest neighbor analysis facilitate accurate disease subtype identification. The landscape is accessible via Oncoscape, an interactive platform, empowering global exploration and application. One Sentence SummaryA landscape built using only Transcriptomic analysis for medulloblastoma and ependymoma reveals novel insights about subtype-specific biology.

bioinformatics↗

bioRxiv2024

Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome.

Meningiomas, the most common intracranial tumor, though mostly benign can be recurrent and fatal. WHO grading does not always identify high risk meningioma and better characterizations of their aggressive biology is needed. To approach this problem, we combined 13 bulk RNA-Seq datasets to create a dimension-reduced reference landscape of 1298 meningiomas. Clinical and genomic metadata effectively correlated with landscape regions which led to the identification of meningioma subtypes with specific biological signatures. Time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape where nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcome. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.

cancer biology↗

bioRxiv2023

An RNA seq-based reference landscape of human normal and neoplastic brain

In order to better understand the relationship between normal and neoplastic brain, we combined five publicly available large-scale datasets, correcting for batch effects and applying Uniform Manifold Approximation and Projection (UMAP) to RNA-seq data. We assembled a reference Brain-UMAP including 702 adult gliomas, 802 pediatric tumors and 1409 healthy normal brain samples, which can be utilized to investigate the wealth of information obtained from combining several publicly available datasets to study a single organ site. Normal brain regions and tumor types create distinct clusters and because the landscape is generated by RNA seq, comparative gene expression profiles and gene ontology patterns are readily evident. To our knowledge, this is the first meta-analysis that allows for comparison of gene expression and pathways of interest across adult gliomas, pediatric brain tumors, and normal brain regions. We provide access to this resource via the open source, interactive online tool Oncoscape, where the scientific community can readily visualize clinical metadata, gene expression patterns, gene fusions, mutations, and copy number patterns for individual genes and pathway over this reference landscape.

bioinformatics↗

bioRxiv2022

Oncogenic role of a developmentally regulated NTRK2 splice variant

Temporally-regulated alternative splicing choices are vital for proper development yet the wrong splice choice may be detrimental. Here we highlight a novel role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in both humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis and forced over-expression of this embryonic pattern causes multiple solid and nonsolid tumors in mice in the context of tumor suppressor loss. TrkB.T1 also emerges the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring TRK fusions. Affinity purification-mass spectrometry (AP-MS) proteomic analysis reveals TrkB.T1 has distinct interactors with known developmental and oncogenic signaling pathways such as Wnt, TGF-{beta}, Hedgehog, and Ras. From alterations in splicing factors to changes in gene expression, the discovery of isoform specific oncogenes with embryonic ancestry has the potential to shape the way we think about developmental systems and oncology.

cancer biology↗