Biology subjects

Eyres, M.

Publications and source records attributed to Eyres, M..

5 recordsLinked to original sources

bioRxiv2025

Hypoxia-induced extracellular matrix changes are conserved in cancer and directly impact radiotherapy benefit

Our overarching aim was to determine how hypoxia affects the extracellular matrix (ECM). Transcriptomic analysis (21,941 patients; 10 cancer types) identified ECM remodelling as the predominant pathway affected by hypoxia. Multi-omics confirmed that hypoxia impacts ECM organisation and collagen degradation; 53 ECM genes were affected, of which 74% were HIF1/HIF2-regulated. Spatial transcriptomics highlighted different hypoxia remodelling processes in tumour and stroma. Five ECM genes commonly affected in tumour and in vitro constituted a signature. This signature was independently prognostic and independently predictive of radiotherapy benefit in multiple malignancies. Patients within either high or low hypoxic-ECM score tertiles benefited from radiotherapy versus surgery. Hypoxic ECMs generated in vitro increased adhesion and decreased migration of cancer cells, an effect enhanced by irradiation. Immunofluorescence demonstrated that hypoxia decreased collagen fibre number, and irradiation decreased cell-ECM interactions. Taken together, these findings demonstrate hypoxia induces pan-cancer ECM changes, directly impacting radiotherapy benefit.

cancer biology↗

bioRxiv2025

Dissecting a biological electron transport network with electrochemistry

Photosynthetic membranes contain complex networks of redox proteins and molecules which direct electrons along various energy-to-chemical interconversion reactions important for sustaining life on Earth. Analysing and disentangling the mechanisms, regulation and interdependencies of these electron transfer pathways is extremely difficult, owing to the large number of interacting components in the native membrane environment. Whilst electrochemistry is well established for studying electron transfer in purified proteins, it has proven difficult to directly wire into proteins within their native membrane environments, and even harder to probe on a systems-level the electron transfer networks they are entangled within. Here, we show how photosynthetic membranes from cyanobacteria can be directly wired to electrodes to access their complex electron transfer networks. Measurements of native membranes with structured electrodes revealed distinctive electrochemical signatures, enabling analysis from the scale of individual proteins to entire biochemical pathways, as well as their interplay. This includes measurements of overlapping photosynthetic and respiratory pathways, the redox activities of membrane-bound quinones, along with validation using in operando spectroscopic measurements. Importantly, we further demonstrated direct extraction of electrons from native membrane-bound Photosystem I at -600 mV, which is [~]1 V more negative than from purified photosystems. This finding opens up opportunities for biotechnologies for solar electricity, fuel and chemical generation. We foresee this electrochemical method being adapted to analyze other photosynthetic and non-photosynthetic membranes, as well as aiding the development of new biocatalytic, biohybrid and biomimetic systems.

biochemistry↗

bioRxiv2021

RASSF1C oncogene elicits amoeboid invasion, cancer stemness and invasive EVs via a novel SRC/Rho axis

Cell plasticity is a crucial hallmark leading to cancer metastasis. Upregulation of Rho/ROCK pathway drives actomyosin contractility, protrusive forces and contributes to the occurrence of highly invasive amoeboid cells in tumors. Cancer stem cells are similarly associated with metastasis, but how these populations arise in tumors is not fully understood. Here we show that the novel oncogene RASSF1C drives mesenchymal to amoeboid transition and stem cell attributes in breast cancer cells. Mechanistically, RASSF1C activates Rho/ROCK via SRC mediated RhoGDI inhibition, resulting in generation of actomyosin contractility. Moreover, we demonstrate that amoeboid cells display the cancer stem cell markers CD133, ALDH1 and the pluripotent marker Nanog; are accompanied by higher invasive potential in vitro and in vivo; and employ extracellular vesicles to transfer the invasive phenotype to target cells and tissue. Importantly, the underlying RASSF1C driven biological processes concur to explain clinical data: namely, methylation of the RASSF1C promoter correlates with better survival in early stage breast cancer patients. Therefore, we propose the use of RASSF1 gene promoter methylation status as a biomarker for patient stratification.

cancer biology↗

bioRxiv2020

TET2 drives 5hmc marking of GATA6 and epigenetically defines pancreatic ductal adenocarcinoma transcriptional subtypes

Background and AimsPancreatic ductal adenocarcinoma (PDAC) is characterised by advanced disease stage at presentation, aggressive disease biology and resistance to therapy resulting in extremely poor five-year survival <10%. PDAC is classified into transcriptional subtypes with distinct survival characteristics, although how these arise is not known. Epigenetic deregulation, rather than genetics, has been proposed to underpin progression but exactly why is unclear and hindered by analysis of clinical samples. MethodsGenome-wide epigenetic mapping of DNA modifications 5-hydroxymethylcytosine (5mc) and 5-hydroxymethylcytosine (5hmc) using oxidative bisulphite sequencing (oxBS). Bioinformatics using iCluster and mutational profiling to identify overlap with transcriptional signatures in FFPE from resected patients and confirmation in vivo. ResultsWe find that more aggressive squamous-like PDAC subtypes result from epigenetic inactivation of loci including GATA6 that promote differentiated classical-pancreatic subtypes. We show that squamous-like PDAC transcriptional subtypes are associated with greater loss of 5hmc due to reduced expression of the 5mc-hydroxylase TET2. Furthermore, we find that SMAD4 directly supports TET2 levels in the pancreas and classical-pancreatic tumors and loss of SMAD4 expression is associated reduced 5hmc, GATA6 and squamous-like tumors. Importantly, enhancing TET2 stability using Metformin and VitaminC/ascorbic acid (AA) restores 5hmc and GATA6 levels, reverting squamous-like tumor phenotypes and WNT-dependence in vitro and in vivo. ConclusionsWe identify epigenetic deregulation of pancreatic differentiation as an underpinning event behind the emergence of transcriptomic subtypes in PDAC. Our data shows that restoring epigenetic control increases biomarkers of classical-pancreatic tumors and raises the possibility that combination of Vitamin C and Metformin may prolong survival in patients with squamous-like pancreatic cancer.

cancer biology↗

bioRxiv2019

RASSF1A Is Required For The Maintenance Of Nuclear Actin Levels

Nuclear actin participates in many essential cellular processes including gene transcription, chromatic remodelling and mRNA processing. Actin shuttles into and out the nucleus through the action of dedicated transport receptors importin-9 and exportin-6, but how this transport is regulated remains unclear. Here we show that RASSF1A is a novel regulator of actin nucleocytoplasmic trafficking and is required for the active maintenance of nuclear actin levels through supporting binding of exportin-6 (XPO6) to RAN GTPase. RASSF1A (Ras association domain family 1 isoform A) is a tumour suppressor gene frequently silenced by promoter hypermethylation in all major solid cancers. Specifically, we demonstrate that endogenous RASSF1A localises to the nuclear envelope (NE) and is required for nucleo-cytoplasmic actin transport and the concomitant regulation of Myocardin-related transcription factor A (MRTF-A), a coactivator of the transcription factor serum response factor (SRF). The RASSF1A/RAN/XPO6/nuclear actin pathway is aberrant in cancer cells where RASSF1A expression is lost and correlates with reduced MTRF/SRF activity leading to cell adhesion defects. Taken together, we have identified a previously unknown mechanism by which the nuclear actin pool is regulated and uncovered a previously unknown link of RASSF1A and MTRF/SRF in tumour suppression.

cell biology↗