Biology subjects

Nathanson, D. A.

Publications and source records attributed to Nathanson, D. A..

4 recordsLinked to original sources

bioRxiv2024

Human Organoid Tumor Transplantation Identifies Functional Glioblastoma - Microenvironmental Communication Mediated by PTPRZ1

Glioblastoma, the most aggressive and deadly form of primary brain cancer, is driven by both intrinsic cellular properties and external factors from the tumor microenvironment. Here, we leverage our novel human organoid tumor transplantation (HOTT) system to explore how extrinsic cues modulate glioblastoma cell type specification, heterogeneity, and migration. We show that HOTT recapitulates the core features of major patient tumor cell types and key aspects of peritumor cell types, while providing a human microenvironment that uniquely enables perturbations in both the patient tumor and its microenvironment. Our exploration of patient tumor - microenvironmental interactions in HOTT highlighted PTPRZ1, a receptor tyrosine phosphatase implicated in tumor migration, as a key player in intercellular communication. We observed that tumor knockdown of PTPRZ1 recapitulated previously described roles in migration and maintaining progenitor identity. Unexpectedly, environmental PTPRZ1 knockdown drove opposite migration and cell fate changes in the tumor, even when the tumor was not manipulated. This previously undiscovered mode of tumor-microenvironmental communication highlights the need to study human glioblastoma in the context of a human microenvironment such as HOTT.

cancer biology↗

bioRxiv2023

Glioblastoma Mesenchymal Transition and Invasion are Dependent on a NF-κB/BRD2 Chromatin Complex

Glioblastoma (GBM) represents the most aggressive subtype of glioma, noted for its profound invasiveness and molecular heterogeneity. The mesenchymal (MES) transcriptomic subtype is frequently associated with therapy resistance, rapid recurrence, and increased tumor-associated macrophages. Notably, activation of the NF-{kappa}B pathway and alterations in the PTEN gene are both associated with this malignant transition. Although PTEN aberrations have been shown to be associated with enhanced NF-{kappa}B signaling, the relationships between PTEN, NF-{kappa}B and MES transition are poorly understood in GBM. Here, we show that PTEN regulates the chromatin binding of bromodomain and extraterminal (BET) family proteins, BRD2 and BRD4, mediated by p65/RelA localization to the chromatin. By utilizing patient-derived glioblastoma stem cells and CRISPR gene editing of the RELA gene, we demonstrate a crucial role for RelA lysine 310 acetylation in recruiting BET proteins to chromatin for MES gene expression and GBM cell invasion upon PTEN loss. Remarkably, we found that BRD2 is dependent on chromatin associated acetylated RelA for its recruitment to MES gene promoters and their expression. Furthermore, loss of BRD2 results in the loss of MES signature, accompanied by an enrichment of proneural signature and enhanced therapy responsiveness. Finally, we demonstrate that disrupting the NF-{kappa}B/BRD2 interaction with a brain penetrant BET-BD2 inhibitor reduces mesenchymal gene expression, GBM invasion, and therapy resistance in GBM models. This study uncovers the role of hitherto unexplored PTEN-NF-{kappa}B-BRD2 pathway in promoting MES transition and suggests inhibiting this complex with BET-BD2 specific inhibitors as a therapeutic approach to target the MES phenotype in GBM.

cancer biology↗

bioRxiv2022

Calculating ATP production rates from oxidative phosphorylation and glycolysis during cell activation

Oxidative phosphorylation and glycolysis are the dominant ATP-generating pathways in mammalian metabolism. The balance between these two pathways is often shifted to execute cell-specific functions in response to stimuli that promote activation, proliferation, or differentiation. However, measurement of these metabolic switches has remained mostly qualitative, making it difficult to discriminate between healthy, physiological changes in energy transduction or compensatory responses due to metabolic dysfunction. We therefore developed a broadly applicable method to calculate ATP production rates from oxidative phosphorylation and glycolysis using Seahorse XF Analyzer data. We quantified the bioenergetic changes observed during macrophage polarization as well as cancer cell adaptation to in vitro culture conditions. Additionally, we detected substantive changes in ATP utilization upon neuronal depolarization and T cell receptor activation that are not evident from steady-state ATP measurements. This method generates a single readout that allows the direct comparison of ATP produced from oxidative phosphorylation and glycolysis in live cells. Additionally, the manuscript provides a framework for tailoring the calculations to specific cell systems or experimental conditions.

biochemistry↗

bioRxiv2021

Pathway-based approach reveals differential sensitivity of glioblastoma to E2F1 inhibition

Targeting glioblastoma (GBM) based on molecular subtyping have not yet translated into successful therapies. Here, we used gene set enrichment analysis (GSEA) to conduct an unsupervised clustering analysis to condense the gene expression data from bulk patient samples and patient-derived gliomasphere lines into new gene lists. We then identified key molecular pathways differentially regulated between tumors. These gene lists associated not only with cell cycle and stemness signatures, but also with cell-type specific markers and different cellular states of GBM. We identified the transcription factor E2F1 as a key regulator of tumor cell proliferation and self-renewal in only the subset of proliferating gliomasphere cultures predicted to be E2F1-activated and validated its functional significance in tumor formation capacity. E2F1 inhibition also sensitized E2F1-activated gliomasphere cultures to radiation treatment. Our findings indicate that a pathway-based approach can be leveraged to deconstruct inter-tumoral heterogeneity and uncover key therapeutic vulnerabilities for targeting GBM.

cancer biology↗