Biology subjects

Gillespie, D.

Publications and source records attributed to Gillespie, D..

4 recordsLinked to original sources

bioRxiv2026

Comprehensive analysis of TEAD inhibition in meningioma identifies MEK and mTOR inhibition as effective combination therapies against resistant lines.

Meningiomas are the most common primary central nervous system tumors in adults, posing a significant burden to society. Although a large percentage of lower-grade meningiomas are curable by surgery or radiation alone, high-grade and a subset of low-grade meningiomas demonstrate recurrences and complications from treatment. Systemic therapies for meningioma remain ineffective, and no targeted treatments are approved. Despite the central role of YAP1/TAZ-TEAD signaling in NF2-deficient/mutant tumors, no studies have systematically examined TEAD inhibition across molecularly defined meningioma subtypes or investigated mechanisms of resistance in this disease. We have recently shown that YAP1/TAZ signaling is an oncogenic driver of meningioma. Here, using established and patient-derived meningioma cell lines, we demonstrate that genetic ablation of YAP1/TAZ suppresses growth in both NF2 mutant and NF2 wild type cell lines, establishing YAP1/TAZ-TEAD signaling as a shared oncogenic dependency. Pharmacologic TEAD inhibition suppressed growth of benign NF2 mutant and a subset of higher-grade NF2 mutant meningiomas, whereas NF2 wild type meningiomas were generally more resistant. RNA-Seq and Western Blot analysis identified compensatory activation of MEK-ERK, mTOR-S6, and FAK signaling in resistant lines exhibit. Importantly, co-targeting these pathways was able to overcome resistance to TEADi and was superior to MEK/mTOR/FAK inhibition alone. These studies provide a compelling proof-of-concept that TEADi represents a novel therapeutic vulnerability in meningioma and reveal adaptive signaling responses that can be therapeutically exploited.

cancer biology↗

bioRxiv2024

Imaging-Guided Metabolic Radiosensitization of Pediatric Rhabdoid Tumors

Tumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRT). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation (OXPHOS) is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved anti-malarial drug, Atovaquone (AVO). We then establish the utility of Oxygen-Enhanced-Multispectral Optoacoustic Tomography (OE-MSOT), a label-free, ionizing radiation-free imaging modality, to visualize and quantify spatiotemporal changes in tumor hypoxia in response to AVO. We show a potent but transient increase in tumor oxygenation upon AVO treatment which results in complete elimination of tumors in all tested mice when combined with 10 Gy radiotherapy, a dose several times lower than the current clinic standard. Finally, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual clinical patient population. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.

bioengineering↗

bioRxiv2020

Passive acoustic methods for tracking the 3D movements of small cetaceans around marine structures

A wide range of anthropogenic structures exist in the marine environment with the extent of these set to increase as the global offshore renewable energy industry grows. Many of these pose acute risks to marine wildlife; for example, tidal energy generators have the potential to injure or kill seals and small cetaceans through collisions with moving turbine parts. Information on fine scale behaviour of animals close to operational turbines is required to understand the likely impact of these new technologies. There are inherent challenges associated with measuring the underwater movements of marine animals which have, so far, limited data collection. Here, we describe the development and application of a system for monitoring the three-dimensional movements of cetaceans in the immediate vicinity of a subsea structure. The system comprises twelve hydrophones and software for the detection and localisation of vocal marine mammals. We present data demonstrating the systems practical performance during a deployment on an operational tidal turbine between October 2017 and October 2019. Three-dimensional locations of cetaceans were derived from the passive acoustic data using time of arrival differences on each hydrophone. Localisation accuracy was assessed with an artificial sound source at known locations and a refined method of error estimation is presented. Calibration trials show that the system can accurately localise sounds to 2m accuracy within 20m of the turbine but that localisations become highly inaccurate at distances greater than 35m. The system is currently being used to provide data on rates of encounters between cetaceans and the turbine and to provide high resolution tracking data for animals close to the turbine. These data can be used to inform stakeholders and regulators on the likely impact of tidal turbines on cetaceans.

ecology↗

bioRxiv2019

Recruiting RyRs to open in a Ca2+ release unit: Single-RyR gating properties make RyR group dynamics

In cardiac myocytes, clusters of type-2 ryanodine receptors (RyR2s) release Ca2+ from the sarcoplasmic reticulum (SR) via a positive feedback mechanism where fluxed Ca2+ activates nearby RyRs. While the general principles of this are understood, less is known about how single-RyR gating properties define the RyR group dynamics in an array of many channels. Here, we examine this using simulations with three models of RyR gating that have identical open probabilities. The commonly-used two-state Markov gating model produces frequent, large, and long Ca2+ release events because the single exponential that defines its open time (OT) and closed time (CT) distributions reproduces the experimental data poorly. In contrast, simulations that utilize complete single-channel OT and CT distributions fit with multiple exponentials produce infrequent Ca2+ release events with far fewer open RyRs. Moreover, when experimentally-measured correlations between single-channel OTs and CTs are included, Ca2+ release events become even smaller. This occurs because the correlations produce a small but consistent bias against recruiting more RyRs to open during the middle of a Ca2+ release event, between the initiation and termination phases (which are unaltered compared to the uncorrelated simulations). Beyond the effects of full OT and CT distributions and OT/CT correlations on SR Ca2+ release, we also show that Ca2+ release events can terminate spontaneously without any reduction in SR [Ca2+] or physical coupling between RyRs when Ca2+ flux is below a threshold value. This both supports and extends the pernicious attrition/induction decay hypothesis that SR Ca2+ release events terminate below a threshold Ca2+ flux.\n\nSTATEMENT OF SIGNIFICANCEThis work provides insights into RyR2-mediated Ca2+ release by a cluster of RyRs interacting only via their fluxed Ca2+. It is shown that: 1) common proxies like the single-RyR open probability versus cytosolic [Ca2+] curve and mean open or closed times are poor predictors of SR Ca2+ release dynamics; 2) Ca2+ release events can self-terminate below a flux threshold without any physical coupling between channels; 3) commonly-used two-state Markov gating models can produce qualitatively different Ca2+ release events (larger and longer) compared to simulations where complete single-channel open and closed time distributions are used; 4) correlations between a RyRs open times and previous closed duration (and vice versa) significantly limit Ca2+ release by tamping down the number of open RyRs.

biophysics↗