Biology subjects

Angus, S. P.

Publications and source records attributed to Angus, S. P..

6 recordsLinked to original sources

bioRxiv2026

ZNF423 depletion induces the integrated stress response and represents a potential vulnerability in NF1-associated MPNST

Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited systemic therapies and represent the leading cause of mortality for individuals with neurofibromatosis type 1 (NF1). Malignant progression can reactivate developmental precursor programs that are largely absent from normal nerve and benign tumors, creating tumor-selective vulnerabilities. Zinc finger protein 423 (ZNF423; also known as OAZ/ROAZ) is a developmentally regulated transcription factor that delays olfactory precursor differentiation and has been implicated in B-cell malignancy. Here, we asked whether ZNF423 is reactivated and functionally required in NF1-associated MPNST. In genetically defined models, Nf1 loss reduced Zfp423 in a benign tumor cell-of-origin context, whereas combined Nf1 and Cdkn2a loss induced marked Zfp423 upregulation during transformation. ZNF423 depletion impaired DNA synthesis and proliferation, induced DNA damage signaling, and activated the integrated stress response (ISR), increasing sensitivity to cytotoxic agents. In an orthotopic MPNST model, shRNA-mediated suppression of ZNF423 reduced tumor initiation in vivo; however, tumors that eventually emerged showed restoration of ZNF423 expression. ZNF423 is developmentally restricted in the peripheral nerve lineage yet elevated in MPNST, with single-cell analyses of patient nerve sheath tumors revealing localized expression restricted to malignant cells rather than SOX10-positive benign tumor cells. These data identify ZNF423 as a putative malignant biomarker, a potential dependency in NF1-MPNST, and nominate downstream stress and genome maintenance pathways as cooperative therapeutic vulnerabilities. STATEMENT OF SIGNIFICANCEZNF423 is a developmentally restricted transcription factor selectively reactivated in NF1-associated malignant peripheral nerve sheath tumors. Targeted ablation triggers the integrated stress response, impairs DNA synthesis, sensitizes cells to chemotherapy and PARP inhibition, and restricts in vivo growth. ZNF423 represents a candidate biomarker and therapeutic vulnerability in this aggressive sarcoma.

cancer biology↗

bioRxiv2026

Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models

Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1), encoded by the gene INPP5D, is a lipid phosphatase that negatively regulates immune receptor signaling in hematopoietic cells and microglia. Here, we describe a pyridyl-pyrazole-piperidine scaffold and the lead compound 3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine (32), which demonstrates SHIP1 target engagement, brain exposure, and evidence of a central pharmacodynamic response in vivo. Structure-activity relationship studies, guided by biochemical and cellular assays using multiple human and murine protein constructs and cells, identified SHIP1-active ligands. A thermal shift assay using full-length SHIP1 was used to assess compounds for cellular target engagement, while studies in IL-4 conditioned THP-1 cells was used to demonstrate changes in downstream AKT signaling. Targeted lipidomics revealed changes in the overall phosphoinositide pool consistent with SHIP1 target engagement and reduction of phospho-AKT levels. In a protein-lipid overlay assay, compound 32 induced changes in the relative association of SHIP1 with multiple phosphatidylinositols on a membrane surface. In high-content cellular imaging assays, compound 32 enhanced the uptake of myelin/membrane debris and fibrillar amyloid by primary murine microglia, phenocopying a genetic model with reduced SHIP1 expression. Finally, oral administration of compound 32 resulted in brain exposure sufficient to alter gene expression and reduce IL-1{beta} levels as pharmacodynamic markers of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimers disease. Collectively, these results define a scaffold with SHIP1 target engagement, CNS exposure, and in vivo activity, providing a foundation for the optimization of brain-penetrant SHIP1 ligands suitable for further mechanistic studies and therapeutic development for the treatment of Alzheimers disease.

pharmacology and toxicology↗

bioRxiv2025

Genetic activation of ERK2 recapitulates core neurodevelopmental features of Rasopathy syndromes in mice

Germline pathogenic variants that activate the Ras/mitogen-activated protein kinase (MAPK) pathway cause neurodevelopmental disorders called Rasopathies. Because many affected proteins directly regulate Ras, causative mutations may alter other Ras-dependent pathways in addition to MAPK signaling. To better understand which Rasopathy sequelae result from hyperactivation of downstream MAP kinases, we engineered mice with a gain-of-function mutation in the terminal MAP kinase gene Mapk1, which encodes ERK2 and is associated with the recently described genetic syndrome MAPK1-related Rasopathy (MRR). Mapk1 mutant mice successfully modeled key aspects of the human MRR phenotype, including small stature, facial dysmorphism, and impaired cognitive function. Importantly, they recapitulated phenotypes identified in Rasopathy models with upstream Ras activation, such as neurofibromatosis type 1 (NF1): oligodendrocyte lineage defects, reactive astrogliosis, memory deficits, and hypersensitivity to sensory stimuli. These findings emphasize the importance of downstream MAPK signaling in the pathophysiology of neurocognitive symptoms observed in Rasopathy syndromes.

genetics↗

bioRxiv2025

RIPK1 regulates beta-cell fate via actions on gene expression and kinase signaling in a mouse model of beta-cell self-reactivity

Type 1 diabetes (T1D) is characterized by autoimmune destruction of pancreatic {beta}-cells, insulin insufficiency, and hyperglycemia. Receptor interacting protein kinase 1 (RIPK1) is a multifunctional regulator of cell fate with kinase and scaffolding functions, and we previously identified RIPKs as regulators of {beta}-cell cytotoxicity in vitro. Here we report that Ripk1 expression is increased in islets from aged non-obese diabetic (NOD) mice and {beta}-cells from T1D donors, suggesting that RIPK1 may drive cytokine- and autoimmune-mediated {beta}-cell demise in T1D. Using NIT-1 {beta}-cells derived from NOD mice, we observed that TNF+IFN{gamma} increase RIPK1 phosphorylation, caspase 3/7 activity, and cell death. In contrast, this cytotoxicity was blocked with small molecule RIPK1 inhibition or in Ripk1 gene-edited (Ripk1{Delta}) {beta}-cells. Co-labeling of caspase 3/7 activation and cell death in single cells revealed protection from caspase-dependent and -independent forms of death in Ripk1{Delta} cells. RNAseq uncovered differential cell death-, immune-, and identity-related gene expression, and kinome profiling identified changes in MAPK, Eph, JAK, and other kinase activity associated with protection from cell death in RIPK1 deficient {beta}-cells. Furthermore, in vitro co-culture assays and in vivo adoptive transfer experiments revealed that NIT-1 Ripk1{Delta} cells were protected from autoimmune destruction by splenocytes isolated from diabetic NOD mice. Collectively, our findings indicate that RIPK1 promotes {beta}-cell demise in response to cytokine and autoimmune stress via actions on gene expression and kinase signaling. Therapeutics targeting RIPK1 may provide novel opportunities for prevention or treatment of autoimmune diabetes.

cell biology↗

bioRxiv2024

A novel induced pluripotent stem cell model of schwann cell differentiation reveals NF2-related gene regulatory networks of the extracellular matrix

Schwann cells are vital to development and maintenance of the peripheral nervous system and their dysfunction has been implicated in a range of neurological and neoplastic disorders, including NF2-related schwannomatosis. We developed a novel human induced pluripotent stem cell (hiPSC) model to study Schwann cell differentiation in health and disease. We performed transcriptomic, immunofluorescence, and morphological analysis of hiPSC derived Schwann cell precursors (SPCs) and terminally differentiated Schwann cells (SCs) representing distinct stages of development. To validate our findings, we performed integrated, cross-species analyses across multiple external datasets at bulk and single cell resolution. Our hiPSC model of Schwann cell development shared overlapping gene expression signatures with human amniotic mesenchymal stem cell (hAMSCs) derived SCs and in vivo mouse models, but also revealed unique features that may reflect species-specific aspects of Schwann cell biology. Moreover, we identified gene co-expression modules that are dynamically regulated during hiPSC to SC differentiation associated with ear and neural development, cell fate determination, the NF2 gene, and extracellular matrix (ECM) organization. By cross-referencing results between multiple datasets, we identified new genes potentially associated with NF2 expression. Our hiPSC model further provides a tractable platform for studying Schwann cell development in the context of human disease.

bioinformatics↗

bioRxiv2017

Proteomic Analysis Defines Kinase Taxonomies Specific For Subtypes Of Breast Cancer

Multiplexed small molecule inhibitors covalently bound to Sepharose beads (MIBs) were used to capture functional kinases in luminal, HER2-enriched and triple negative, basal-like and claudin-low breast cancer cell lines and tumors. Kinase MIB-binding profiles at baseline without perturbation proteomically distinguished the four breast cancer subtypes. Kinases lacking defined functions in breast cancer were highly represented in the MIB-binding taxonomies. We show that these understudied kinases, whose disease associations and pharmacology are generally unexplored, are integrated in kinase signaling subnetworks with kinases that have been previously well characterized in breast cancer. Computationally it was possible to define subtypes using profiles of less than 50 of the more than 300 kinases bound to MIBs that included understudied as well as metabolic and lipid kinases. Furthermore, analysis of MIB-binding profiles established potential functional annotations for these understudied kinases. Thus, comprehensive MIBs-based capture of kinases provides a unique proteomics-based method for integration of poorly characterized kinases of the understudied kinome into functional subnetworks in breast cancer cells and tumors that is not possible using genomic strategies. The MIB-binding profiles readily defined subtype-selective differential adaptive kinome reprogramming in response to targeted kinase inhibition, demonstrating how MIB profiles can be used in determining dynamic kinome changes that result in subtype selective phenotypic state changes.

cancer biology↗