Biology subjects

West, L. C.

Publications and source records attributed to West, L. C..

6 recordsLinked to original sources

bioRxiv2026

Tumor cell-intrinsic mtDNA instability drives cGAS-dependent temporal remodeling of the melanoma immune microenvironment

Mitochondrial DNA (mtDNA) instability is an emerging feature of cancer, yet its biological effects on the tumor microenvironment (TME) and tumor progression remain incompletely defined. Using melanocyte-specific conditional silencing of mitochondrial transcription factor A (TFAM) in an autochthonous BrafV600E/Pten-/- melanoma model, we demonstrate that tumor cell-intrinsic mtDNA instability accelerates melanoma growth and metastatic dissemination in a cGAS-dependent manner. Transcriptomic profiling of early and late tumor stages revealed that mtDNA instability drives temporal remodeling of the tumor microenvironment (TME), characterized by an early type I interferon (IFN)-rich inflammatory state that licenses immunoregulatory programs as tumors progress. Tumor-associated macrophages emerged as the principal immune cell type reshaped by tumor cell-intrinsic mtDNA stress signaling, with early enrichment of inflammatory states and a shift toward efferocytosis-associated, tissue-adaptive states. The early mtDNA instability-associated macrophage signatures mapped to human melanoma states associated with favorable survival and therapy response, whereas the late signatures mapped to states associated with poor prognosis and therapy resistance across independent cohorts. Anti-PD-1 treatment delayed progression of mtDNA-instable tumors, consistent with a therapeutic sensitivity window associated with the early IFN-rich immune state. These findings establish tumor cell-intrinsic mtDNA instability as a driver of temporal immune-stromal remodeling that promotes melanoma progression and shapes therapeutic response.

immunology↗

bioRxiv2026

Genuinely Blind Identification of Sleep Spindles through Trispectral Modulation Analysis

Sleep spindles, transient 11-16 Hz oscillatory bursts, are a defining electrographic feature of non-rem (NREM) sleep and a key biomarker of sleep physiology. A need for efficient and reliable identification of spindles motivates a large literature on automated detection algorithms. In this literature, annotation by trained sleep specialists remains the gold standard against which automated methods are trained, tuned and evaluated. However, inter-scorer agreement among experts is modest, which leaves a significant role for subjective judgment in the definition of a spindle. Finding objective, scorer-independent, criteria for identifying spindles remains an unresolved challenge. We report here a robust, highly specific, and previously unrecognized signature of spindle activity in the fourth-order spectrum (trispectrum), from which we identify the presence of spindles, characterize their waveforms, and obtain an optimal detection filter through a decomposition of the trispectrum (HOSD). Although it is a strictly blind, data-driven method, HOSD-based spindle identification and detection agrees well with expert annotation (median AUROC ~0.9), yet identifies many more events at the native threshold than both human scorers and comparison detectors. Many of these additional detections are confirmed as meeting AASM spindle criteria by four blinded specialists, demonstrating that spindle-like oscillatory bursting is prevalent below conventional human and automated detection thresholds. We observe that N2 sleep is distinguished principally by high-amplitude bursts, while low-amplitude bursting persists throughout NREM sleep, being globally suppressed only in REM sleep. We also describe robust identification of recording-specific spindle waveform properties such as frequency deceleration.

neuroscience↗

bioRxiv2022

ZBP1 sequesters cGAS in the cytoplasm and sustains type I interferon responses to mitochondrial DNA

Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of mtDNA detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability leads to Z-form mtDNA accumulation. Z-DNA Binding Protein 1 (ZBP1) stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I interferon (IFN-I) signaling. Increased mitochondrial Z-DNA, ZBP1 expression, and IFN-I responses are observed in cardiomyocytes after exposure to Doxorubicin, a first-line chemotherapeutic agent that induces frequent cardiotoxicity in cancer patients. Strikingly, mice lacking ZBP1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity. Our findings reveal ZBP1 as a cooperative partner for cGAS that sustains IFN-I responses to mitochondrial genome instability and highlight ZBP1 as a potential target in heart failure and other disorders where mtDNA stress contributes to interferon-related pathology.

immunology↗

bioRxiv2020

Type I interferon potentiates metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune crosstalk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA (mtDNA) instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces healthspan, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which increases oxidative stress, enhances pro-inflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyper-inflammatory phenotypes by restoring Nrf2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related diseases and aging.

immunology↗

bioRxiv2020

Innate immune signaling and sex differences contribute to neurocognitive impairment, neuroinflammation, and mitochondrial rewiring in a mouse model of Gulf War illness

Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting approximately 30 percent of the nearly 700,000 veterans of the 1991 Persian Gulf War. Recent studies have revealed that GWI-related chemical (GWIC) exposure promotes immune activation and metabolic rewiring, which correlate with neurocognitive impairments and other symptoms of GWI. However, the molecular mechanisms and signaling pathways linking GWIC to inflammation, metabolic alterations, and neurological symptoms remain unclear. Mitochondrial dysfunction has been documented in veterans with GWI and rodent models, and because mitochondria are key immune regulators, we hypothesized that alterations to mitochondria-immune crosstalk could contribute to the development of GWI-related symptoms. Here we show that acute exposure of murine macrophages to GWIC alters mitochondrial respiration and potentiates innate immune signaling and inflammatory cytokine secretion. Using an established mouse model of GWI, we report that neurobehavioral changes, neuroinflammation, and mitochondrial protein rewiring are attenuated in mice lacking the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) and NOD-, LRR- or pyrin domain-containing protein 3 (NLRP3) innate immune pathways. Finally, we report sex differences in response to GWIC, with female mice showing more pronounced cognitive impairment, neuroinflammation, and mitochondrial protein alterations in the brain compared to male mice. Our results provide novel information on sex differences in this model and suggest that STING and NLRP3 are key mediators of the cognitive impairment, inflammation, and mitochondrial dysfunction observed in GWI.

neuroscience↗

bioRxiv2020

A Versatile Soluble Siglec Scaffold for Sensitive and Quantitative Detection of Glycan Ligands

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are immunomodulatory receptors that are regulated by their glycan ligands. A growing connection between Siglecs and human disease motivates improved methods to detect Siglec ligands. Here, we describe a new versatile set of Siglec-Fc proteins for glycan ligand detection. Enhanced sensitivity and selectivity are enabled through multimerization and avoiding Fc receptors, respectively. Using these Siglec-Fc proteins, Siglec ligands were systemically profiled on healthy and cancerous cells and tissues, revealing many unique patterns. Additional features enable the production of small, homogenous Siglec fragments and development of a quantitative ligand-binding mass spectrometry assay. Using this assay, the ligand specificities of several Siglecs were clarified. For CD33, we demonstrate that it recognizes both 2-3 and 2-6 sialosides in solution and on cells, which has implications for its link to Alzheimers disease susceptibility. These soluble Siglecs reveal the abundance of their glycan ligands on host cells as self-associated molecular patterns.

biochemistry↗