Biology subjects

McKenzie, M.

Publications and source records attributed to McKenzie, M..

4 recordsLinked to original sources

bioRxiv2025

Fast and Furious: Metabolic Pathways Fuelling Devil Facial Tumour Disease

Devil Facial Tumour Diseases (DFTD), threatening Tasmanian devils, consist of two distinct transmissible cancers, DFT1 and DFT2, with differing origins and geographic spread. We investigated the metabolic differences between DFT1 and DFT2, examining cell viability, metabolic outputs, and bulk gene expression. Using both DFT1 and DFT2 cell lines and biopsies, we found that glycolysis, oxidative phosphorylation, glutamate metabolism and fatty acid synthesis are all essential for the survival of both tumour types. However, DFT2 exhibited higher rates of glycolysis and lactate generation compared to DFT1. This coincided with elevated ATP production, cholesterol biosynthesis and ROS generation, as well as an increased reliance on fatty acid metabolism. Furthermore, DFT2 is less metabolically adaptable than DFT1, being unable to switch to oxidative phosphorylation as DFT1 can when required. These metabolic changes in DFT2, in conjunction with its higher growth rate, suggests a more aggressive cancer phenotype than DFT1. Our findings highlight distinct metabolic adaptations in DFT2 that may contribute to its competitive advantage.

cancer biology↗

bioRxiv2023

WNT Signalling Promotes NF-κB Activation and Drug Resistance in KRAS-Mutant Colorectal Cancer

Approximately 40% of colorectal cancer (CRC) cases are characterized by KRAS mutations, rendering them insensitive to most CRC therapies. While the reasons for this resistance remain incompletely understood, one key aspect is genetic complexity: in CRC, oncogenic KRAS is most commonly paired with mutations that alter WNT and P53 activities ("RAP"). Here, we demonstrate that elevated WNT activity upregulates canonical (NF-{kappa}B) signalling in both Drosophila and human RAS mutant tumours. This upregulation required Toll-1 and Toll-9 and resulted in reduced efficacy of RAS pathway targeted drugs such as the MEK inhibitor trametinib. Inhibiting WNT activity pharmacologically significantly suppressed trametinib resistance in RAP tumours and more genetically complex RAP-containing patient avatar models. WNT/MEK drug inhibitor combinations were further improved by targeting brm, shg, ago, rhoGAPp190 and upf1, highlighting these genes as candidate biomarkers for patients sensitive to this duel approach. These findings shed light on how genetic complexity impacts drug resistance and proposes a therapeutic strategy to reverse this resistance.

cancer biology↗

bioRxiv2022

Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in obesity

There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimers disease. While some common aetiological mechanisms are known, the role of amyloid beta 42 (A{beta}42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases A{beta}42, which is increased from adipose tissue of obese mice and is associated with higher plasma A{beta}42. Increasing circulating A{beta}42 levels in non-obese mice had no effect on systemic glucose homeostasis but had obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. These effects on cardiac function were not observed when circulating levels of the closely related A{beta}40 isoform were increased. Administration of an A{beta} neutralising antibody prevented obesity-induced cardiac dysfunction and hypertrophy. Furthermore, A{beta} neutralising antibody administration in established obesity prevented further deterioration of cardiac function. Multi-contrast transcriptomic analyses revealed that A{beta}42 impacted pathways of mitochondrial metabolism and exposure of cardiomyocytes to A{beta}42 inhibited mitochondrial function. These data reveal a role for systemic A{beta}42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimers disease could be effective in combating obesity-induced heart failure.

physiology↗

bioRxiv2019

Fishing for mammals: landscape-level monitoring of terrestrial and semi-aquatic communities using eDNA from lotic ecosystems

O_LIEnvironmental DNA (eDNA) metabarcoding has revolutionised biomonitoring in both marine and freshwater ecosystems. However, for semi-aquatic and terrestrial animals, the application of this technique remains relatively untested.\nC_LIO_LIWe first assess the efficiency of eDNA metabarcoding in detecting semi-aquatic and terrestrial mammals in natural lotic ecosystems in the UK by comparing sequence data recovered from water and sediment samples to the mammalian communities expected from historical data. Secondly, we evaluate the detection efficiency of eDNA samples compared to multiple conventional non-invasive survey methods (latrine surveys and camera trapping) using occupancy modelling.\nC_LIO_LIeDNA metabarcoding detected a large proportion of the expected mammalian community within each area. Common species in the areas were detected at the majority of sites. Several key species of conservation concern in the UK were detected by eDNA in areas where authenticated records do not currently exist, but potential false positives were also identified for several non-native species.\nC_LIO_LIWater-based eDNA samples provided comparable results to conventional survey methods in per unit of survey effort for three species (water vole, field vole, and red deer) using occupancy models. The comparison between survey effort to reach a detection probability of [≥]0.95 revealed that 3-6 water replicates would be equivalent to 3-5 latrine surveys and 5-30 weeks of single camera deployment, depending on the species.\nC_LIO_LISynthesis and Applications. eDNA metabarcoding represents an extremely promising tool for monitoring mammals, allowing for the detection of multiple species simultaneously, and provides comparable results to widely-used conventional survey methods. eDNA from freshwater systems delivers a terrestrial dividend by detecting both semi-aquatic and terrestrial mammalian communities, and provides a basis for future monitoring at a landscape level over larger spatial and temporal scales (i.e. long-term monitoring at national levels).\nC_LI

ecology↗