Biology subjects

Cavanagh, B.

Publications and source records attributed to Cavanagh, B..

4 recordsLinked to original sources

bioRxiv2026

Metabolic Reprogramming of Human Macrophages Drives the Formation of Hybrid M1/M2 Pro-Regenerative Extracellular Vesicles

The coordinated activity of macrophages is essential for bone repair, with pro-inflammatory M1 macrophages driving early responses and anti-inflammatory M2 macrophages supporting later tissue remodeling. While both phenotypes are required, prolonged persistence of either subtype can impair healing, underscoring the correct transition between the two states. Macrophage polarization is closely linked to cellular metabolism, and human macrophages display distinct metabolic profiles. Macrophage-derived extracellular vesicles (EVs) carry bioactive cargo and reflect parental polarization, influencing recipient cell function. This raises critical questions about how metabolic regulation influences human macrophage function, their EVs and their effect on angiogenesis and osteogenesis. This study investigates EVs derived from polarized primary human macrophages and from macrophages exposed to DASA-58, a small molecule which activates the metabolic enzyme pyruvate kinase M2 (PKM2). Alterations in macrophage metabolism modifies the molecular cargo of their EVs, including microRNAs (miRNAs), to modulate regenerative activity. These findings demonstrate that human macrophage-derived EVs exert metabolically dependent effects on angiogenesis and osteogenesis, and that metabolic modulation enables the generation of EVs with hybrid pro-regenerative properties intermediate between M1 and M2. This establishes metabolic reprogramming within human macrophages using small molecules as a strategy to engineer novel phenotypes and EVs for bone repair.

immunology↗

bioRxiv2024

Mitochondrial metabolism is a key determinant of chemotherapy sensitivity in Colorectal Cancer

Therapy resistance is attributed to over 80% of cancer deaths per year emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. Here, we investigate the transcriptional responses of CRC cells to 5FU treatment, revealing significant metabolic reprogramming towards heightened mitochondrial activity. Utilizing CRC models, we demonstrate sustained enhancement of mitochondrial biogenesis and function following 5FU treatment, leading to resistance in both in vitro and in vivo settings. Furthermore, we show that targeting mitochondrial metabolism, specifically by inhibiting Complex I (CI), sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, our analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.

cancer biology↗

bioRxiv2020

TRAIL signalling promotes entosis in colorectal cancer

Entosis is a form of non-phagocytic cell-in-cell (CIC) interaction where a living cell enters into another. Tumours show evidence of entosis, however factors controlling entosis remain to be elucidated. Here we find that the death receptor ligand TRAIL is a potent activator of entosis in colon cancer cells. CLEM/3D confocal microscopy analysis revealed ultrastructural features of entosis and subsequent entotic cell death of inner cells upon TRAIL treatment. Induction of entosis and apoptosis by TRAIL were mutually exclusive events but both required the presence of caspase-8. Bax/Bak double knock-out or caspase inhibition altered the fate of inner cells from entotic cell death to survival and escape. Analysis of colorectal cancer tumours showed a significant association between expression levels of TRAIL and CICs. Notably, the presence of CICs in the invasive front regions of colorectal tumours was significantly correlated with adverse patient prognosis.

cancer biology↗

bioRxiv2019

Potent and lasting seizure suppression by systemic delivery of antagomirs targeting miR-134 timed with blood-brain barrier disruption

RNA therapies such as oligonucleotides (OGNs) offer precision treatments for a variety of neurological diseases, including epilepsy but their deployment is hampered by the blood brain barrier (BBB). Here we used brain imaging and assays of serum proteins and tracer extravasation, to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically-injected antisense OGNs targeting microRNA-134 (Ant-134) into the brain parenchyma. A single intraperitoneal injection of Ant-134 two hours after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at three months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces disease-modifying effects after systemic injection in mice when timed with BBB disruption and may be a clinically-viable approach for this and other disease-modifying microRNA therapies.

neuroscience↗