Biology subjects

Thomas, F.

Publications and source records attributed to Thomas, F..

At least 19 recordsLinked to original sources

bioRxiv2026

Aberrant CD4+ T cell refeeding response impairs neuro-immune crosstalk in Parkinson's disease

T cells modulate disease associated neuroinflammation in Parkinsons disease (PD). We report that circulating CD4+ T cells from people with PD have a dysregulated transcriptional and cytokine response to fasting and refeeding and an altered metabolic profile. The CD4+ T cell secretome mediates a metabolic program in neurons that is impaired in PD, revealing dysfunctional neuro-immune signalling that may contribute to disease pathology.

neuroscience↗

bioRxiv2025

The Cost of Fame: Strong Biases in Comparative Oncology of Captive Species

Comparative oncology is a rapidly expanding field that seeks to explain variation in cancer risk across species by examining trends between tumour prevalence and key risk factors such as body mass, longevity, life history traits, and mutation rates. These trends are then used to address fundamental questions in the field, including the discovery of potential novel anti-cancer therapies, improvements to species conservation efforts, and understanding how cancer has influenced the evolution of multicellularity. They thus must be robust. This study demonstrates that when estimated on captive species those trends are heavily influenced by their scientific and public popularity, and that accounting for this bias can substantially alter their direction and magnitude. Hence, we reanalysed published captive vertebrate datasets examining the associations between neoplasia, malignancy, and lethal tumour prevalences with body mass, longevity, life history traits, and germinal cells mutation rates. When we included proxies of species popularity in our analyses, the previously reported weak effect of body mass on tumour and malignancy prevalences disappeared entirely. Similarly, the previously reported positive relationship between germline mutation rate and cancer mortality was eliminated after controlling for popularity bias. For life history traits, the effect of clutch size on cancer neoplasia and malignancy prevalences in birds doubled in magnitude, and while the negative trend between gestation length and tumour prevalence in mammals was not greatly affected, our analyses revealed that baseline tumour prevalences were underestimated for popular animals. Finally, the previously observed association between hemochorial placentation and cancer mortality in mammals was eliminated when confounding variables were included. Collectively, these results demonstrate that current comparative analyses based on tumour prevalence in captive animals are heavily influenced by species scientific and public popularities. Future studies utilising such datasets should incorporate measures of species popularity as confounding variables to ensure more robust conclusions and misleading research directions.

cancer biology↗

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↗

bioRxiv2024

Tumor-associated macrophages confer resistance to chemotherapy (Trifluridine/Tipiracil) in digestive cancers by overexpressing Thymidine Phosphorylase

Pyrimidine analogs are part of the first-line chemotherapy regimen for gastrointestinal cancers. Trifluridine combined with tipiracil, a specific thymidine phosphorylase inhibitor, in TAS-102 has recently emerged as a potential alternative in the face of primary or secondary chemoresistance to 5-fluorouracil. Despite its promise, in the current study, we report that macrophage-specific overexpression of thymidine phosphorylase results in macrophage-induced chemoresistance to TAS-102 that is insensitive to tipiracil inhibition. In addition, we demonstrate the human specificity of this mechanism, as mouse macrophages do not express significant levels of thymidine phosphorylase. To study the importance of macrophages in chemoresistance to trifluridine, we developed a humanized mouse model with tumor-implanted human macrophages and demonstrated their important role in treatment resistance to pyrimidine analogs. We also showed in human colorectal cancer that macrophages represent a major source of thymidine phosphorylase expression leading to chemoresistance. SignificanceThymidine phosphorylase overexpression in TAMs confers chemoresistance to TAS-102 in digestive cancers.

pathology↗

bioRxiv2024

Binocular processing facilitates escape behavior through multiple pathways to the superior colliculus

The superior colliculus (SC) is the main brain region regulating innate defensive behaviors to visual threat. Yet, how the SC integrates binocular visual information and to what extent binocular vision drives defensive behaviors is unknown. Here, we show that binocular vision facilitates visually-evoked escape behavior. Furthermore, we find that SC neurons respond to binocular visual input with diverse synaptic and spiking responses, and summate visual inputs largely sublinearly. Using pathway-specific optogenetic silencing we find that contralateral and ipsilateral visual information is carried to binocular SC neurons through retinal, interhemispheric and corticotectal pathways. These pathways carry binocular visual input to the SC in a layer-specific manner, with superficial layers receiving visual information through retinal input, whereas intermediate and deep layers rely on interhemispheric and corticotectal pathways. Together, our data shed light on the cellular and circuit mechanisms underlying binocular visual processing in the SC and its role in escape behavior.

neuroscience↗

bioRxiv2024

Universal protection of allogeneic cell therapies from natural killer cells via CD300a agonism

Immunogenicity limits the persistence of off-the-shelf, allogeneic cell therapies and transplants. While ablation of human leukocyte antigen (HLA) removes most T cell and humoral alloreactivity, no solution has enabled universal protection against the resulting natural killer (NK) cell response. Here, we engineered Trans Antigen Signaling Receptors (TASR) as a new class of NK inhibitory ligands and discovered CD300a, a previously inaccessible receptor, as a functional target. CD300a TASR outperformed leading alternative strategies in focused screens, including CD47 and HLA-E, and was solely capable of universally protecting allogeneic T cells against a large human cohort (45/45 donors), spanning diverse demographics and NK cell phenotypes. A model allogeneic T cell therapy co-expressing an anti-CD19 Chimeric Antigen Receptor (CAR) and CD300a TASR, produced using multiplexed non-viral integration, exhibited enhanced B cell killing potency under allogeneic immune pressure. CD300 TASR represents a universal solution to NK alloreactivity, broadening the population that could be effectively treated by next-generation allogeneic cell therapies. CategoryImmunobiology and Immunotherapy Key PointsO_LIAn engineered CD300a agonist ligand (CD300a TASR) universally protects HLA-deficient allogeneic T cells from NK-mediated rejection. C_LIO_LICD300a TASR is more protective in CMV seropositive hosts than HLA-E ligand and enhances CAR-T efficacy under allogeneic immune pressure. C_LI

immunology↗

bioRxiv2024

De novo evolution of transmissible tumors in Hydra

While most cancers are not transmissible, there are rare cases where cancer cells have acquired the ability to spread vertically or horizontally to other individuals, and sometimes species, causing epidemics in their hosts. However, as these transmissible cancers are usually detected once they are relatively well disseminated in host populations, the conditions associated with their origin remain poorly understood. Using the freshwater cnidarian Hydra oligactis, which exhibits spontaneous tumor development that in some strains became vertically transmitted, this study presents the first experimental observation of the evolution of a transmissible tumor. Specifically, we assessed the initial vertical transmission rate of spontaneous tumors and explored the potential for optimizing this rate through artificial selection. One of the hydra strains, which evolved transmissible tumors over five generations, was characterized by analysis of cell type and microbiome, as well as assessment of life-history traits. Our findings indicate that tumor transmission can be immediate for some strains and can be enhanced by selection. The resulting tumors are characterized by overproliferation of large interstitial stem cells and, in contrast with other transmissible tumors on Hydra, are not associated with a specific microbiome. Furthermore, although tumor transmission has only been established over 5 generations, it was sufficient to alter life-history traits in the host, suggesting a compensatory response. This work, therefore, makes the first contribution to understanding the conditions of transmissible cancer emergence and their short-term consequences for the host.

evolutionary biology↗

bioRxiv2024

Metabolic reprogramming of hypoxic tumour-associated macrophages through CSF-1R targeting favours treatment efficiency in colorectal cancers

Tumor-associated macrophages participate in the complex network of support that favors tumor growth. Among the various strategies that have been developed to target these cells, blockade of the CSF-1R receptor is one of the most promising one. Here, we characterize the resulting state of human macrophages exposed to a CSF-1R kinase inhibitor. We find that CSF-1R receptor inhibition in human macrophages is able to impair cholesterol synthesis, fatty acid metabolism and hypoxia-driven expression of dihydropyrimidine dehydrogenase, an enzyme responsible for the 5-fluorouracil macrophage-mediated chemoresistance. We show that this inhibition of the CSF-1R receptor leads to a downregulation of the expression of SREBP2, a transcription factor that controls cholesterol and fatty acid synthesis. We also show that the inhibition of ERK1/2 phosphorylation resulting from targeting the CSF-1R receptor destabilizes the expression of HIF2 in hypoxia resulting in the downregulation of dihydropyrimidine dehydrogenase expression restoring the sensitivity to 5-fluorouracil in colorectal cancer. These results reveal the unexpected metabolic rewiring resulting from the CSF-1R receptor targeting of human macrophages in tumors.

immunology↗

bioRxiv2024

Consequences of Cancer on Zebrafish Danio rerio: Insights into Sex Determination, Sex Ratio, and Offspring Survival.

Offspring sex ratio has been proposed as an indicator of the risk of developing certain cancers in humans, but offspring sex ratio may also be a consequence of the disease. In this study, we delve into this subject using the fish Danio rerio as a model system. First, we explore whether inducing skin cancer at an early stage of the hosts life (embryonic stage) has the potential to influence sex determination and/or sex-specific mortality. Second, we investigate whether the sex ratio in offspring produced by tumor-bearing adult females differs from that of healthy females. Third, we compare the survival (until sexual maturity) of offspring produced by cancerous and non-cancerous females. We found that skin cancer did not influence sex ratio in both experiments. However, consistent with previous studies on other model systems, the survival of offspring from cancerous females was higher, suggesting that diseased females allocate more resources to current reproductive efforts compared to their healthy counterparts. This study makes a significant contribution to our understanding of the ecological and evolutionary consequences of host-tumor interactions in animals.

evolutionary biology↗

bioRxiv2023

Novel laminarin-binding CBMs in multimodular proteins of marine Bacteroidota feature prominently in phytoplankton blooms

The {beta}-(1,3)-glucan laminarin functions as storage polysaccharide in marine stramenophiles such as diatoms. Laminarin is abundant, water-soluble and structured simply, making it an attractive substrate for marine bacteria. As a consequence, many marine bacteria have developed competitive strategies to scavenge and decompose laminarin, which involves carbohydrate-binding modules (CBMs) as key players. We therefore functionally and structurally characterized two yet unassigned domains as laminarin-binding CBMs in multimodular proteins from our model bacterium Christiangramia forsetii KT0803T, hereby unveiling the novel laminarin-binding CBM families CBMxx and CBMyy (official CAZy numbering will be provided upon acceptance of the manuscript in a peer-reviewed journal). We discovered four CBMxx repeats in a surface glycan-binding protein (SGBP) and a single CBMyy combined with a glycoside hydrolase module from family 16 (GH16_3). Our analyses revealed that both modular proteins have an elongated shape, and that the GH16_3 displayed a higher flexibility than the SGBP. While motility of both polypeptide chains may facilitate recognition and/or degradation of laminarin, constraints in the SGBP may support docking of laminarin onto the bacterial surface. The exploration of bacterial metagenome-assembled genomes (MAGs) from phytoplankton blooms in the North Sea revealed that both laminarin-binding CBM families are widely distributed among marine Bacteroidota, illustrating the high adaptability of modularity in sugar-binding and -degrading proteins. High expression of CBMxx- and CBMyy-containing proteins during phytoplankton blooms further underpins their importance in marine laminarin usage.

biochemistry↗

bioRxiv2023

Marine transmissible cancer navigates urbanised waters, threatening to spillover

Inter-individual transmission of cancer cells represents a unique form of microparasites increasingly reported in marine bivalves. In this study, we sought to understand the ecology of the propagation of Mytilus trossulus Bivalve Transmissible Neoplasia 2 (MtrBTN2), a transmissible cancer affecting four Mytilus mussel species worldwide. We investigated the prevalence of MtrBTN2 in the mosaic hybrid zone of M. edulis and M. galloprovincialis along the French Atlantic coast, sampling contrasting natural and anthropogenic habitats. We observed a similar prevalence in both species, likely due to the spatial proximity of the two species in this region. Our results showed that ports had higher prevalence of MtrBTN2, with a possible hotspot observed at a shuttle landing dock. No cancer was found in natural beds except for two sites close to the hotspot, suggesting spillover. Ports may provide favourable conditions for the transmission of MtrBTN2, such as high mussel density, stressful conditions, sheltered and confined shores, or buffered temperatures. Ships may also spread the disease through biofouling. Our results suggest ports may serve as epidemiological hubs, with maritime routes providing artificial gateways for MtrBTN2 propagation. This highlights the importance of preventing biofouling on docks and ship hulls to limit the spread of marine pathogens hosted by fouling species.

ecology↗

bioRxiv2023

Transcriptomics of mussel transmissible cancer MtrBTN2 reveals accumulation of multiple cancerous traits and oncogenic pathways shared among bilaterians

Transmissible cancer cell lines are rare biological entities giving rise to diseases at the crossroads of cancer and parasitic diseases. These malignant cells have acquired the amazing capacity to spread from host to host. They have been described only in dogs, Tasmanian devils and marine bivalves. The Mytilus trossulus Bivalve Transmissible Neoplasia 2 (MtrBTN2) lineage has even acquired the capacity to spread inter-specifically between marine mussels of the Mytilus edulis complex worldwide. To identify the oncogenic processes underpinning the biology of these atypical cancers we performed transcriptomics of MtrBTN2 cells. Differential expression, enrichment, protein-protein interaction network, and targeted analyses were used. Overall, our results suggest the accumulation of multiple cancerous traits that way be linked to the long-term evolution of MtrBTN2. We also highlight that vertebrate and lophotrochozoan cancers could share a large panel of common drivers, which supports the hypothesis of an ancient origin of oncogenic processes in bilaterians.

cancer biology↗

bioRxiv2022

Pan-cancer proteomic map of 949 human cell lines reveals principles of cancer vulnerabilities

The proteome provides unique insights into biology and disease beyond the genome and transcriptome. Lack of large proteomic datasets has restricted identification of new cancer biomarkers. Here, proteomes of 949 cancer cell lines across 28 tissue types were analyzed by mass spectrometry. Deploying a clinically-relevant workflow to quantify 8,498 proteins, these data capture evidence of cell type and post-transcriptional modifications. Integrating multi-omics, drug response and CRISPR-Cas9 gene essentiality screens with a deep learning-based pipeline revealed thousands of protein-specific biomarkers of cancer vulnerabilities. Proteomic data had greater power to predict drug response than the equivalent portion of the transcriptome. Further, random downsampling to only 1,500 proteins had limited impact on predictive power, consistent with protein networks being highly connected and co-regulated. This pan-cancer proteomic map (ProCan-DepMapSanger), available at https://cellmodelpassports.sanger.ac.uk, is a comprehensive resource revealing principles of protein regulation with important implications for future clinical studies.

systems biology↗

bioRxiv2021

Metabolic strategies of sharing pioneer bacteria mediating fresh macroalgae breakdown

Macroalgae represent huge amounts of biomass worldwide, largely recycled by marine heterotrophic bacteria. We investigated the strategies of "pioneer" bacteria within the flavobacterial genus Zobellia to initiate the degradation of fresh brown macroalgae, which has received little attention compared to the degradation of isolated polysaccharides. Zobellia galactanivorans DsijT could use macroalgae as a sole carbon source and extensively degrade algal tissues without requiring physical contact, via the secretion of extracellular enzymes. This indicated a sharing behaviour, whereby pioneers release public goods that can fuel other bacteria. Comparisons of eight Zobellia strains, and strong transcriptomic shifts in Z. galactanivorans cells using fresh macroalgae vs. isolated polysaccharides, revealed potential overlooked traits of pioneer bacteria. Besides brown algal polysaccharide degradation, they notably include stress resistance proteins, type IX secretion system proteins and novel uncharacterized Polysaccharide Utilization Loci. Overall, this work highlights the relevance of studying fresh macroalga degradation to fully understand the niche, metabolism and evolution of pioneer degraders, as well as their cooperative interactions within microbial communities, as key players in macroalgal biomass turnover.

microbiology↗

bioRxiv2020

Indigenous plants promote insect biodiversity in urban greenspaces

The contribution of urban greenspaces to support biodiversity and provide benefits for people is increasingly recognised. However, ongoing management practices still favour (1) vegetation oversimplification, often limiting greenspaces to lawns and tree canopy rather than multi-layered vegetation that includes under and midstorey; and (2) the use of nonnative plant species. These practices likely hinder the potential of greenspaces to sustain indigenous biodiversity, particularly for taxa like insects, that rely on plants for food and habitat. Yet, little is known about which plant species may maximise positive outcomes for taxonomically and functionally diverse insect communities in urban greenspaces. Additionally, while urban environments are expected to experience high rates of introductions, quantitative assessments of the relative occupancy of indigenous vs. introduced insect species in greenspace are rare - hindering understanding of how greenspace management may promote indigenous biodiversity while limiting the establishment of introduced insects. Using a hierarchically replicated study design across 15 public parks, we recorded occurrence data from 552 insect species on 133 plant species - differing in planting design element (lawn, midstorey and tree canopy), midstorey growth form (forbs, lilioids, graminoids and shrubs) and origin (nonnative, native and indigenous) - to assess: (1) the relative contributions of indigenous and introduced insect species and (2) which plant species sustained the highest number of indigenous insects. Our data indicates that the insect community was predominately composed of indigenous rather than introduced species. Our findings further highlight the core role of multi-layered vegetation in sustaining high insect biodiversity in urban areas, with indigenous midstorey and canopy representing key elements to maintain rich and functionally diverse indigenous insect communities. Intriguingly, graminoids supported the highest indigenous insect richness across all studied growth forms by plant origin groups. Taken together, our study emphasise the opportunity posed by indigenous understory and midstorey plants, particularly indigenous graminoids in our study area, to promote indigenous insect biodiversity in urban greenspaces. Our work provides a blueprint and stimulus for built-environment professionals to incorporate into their practice plant species palettes that foster a larger presence of indigenous over regionally native or nonnative plant species, whilst incorporating a broader mixture of midstorey growth forms.

ecology↗

bioRxiv2019

Loss of cerebellar function selectively affects intrinsic rhythmicity of eupneic breathing

Respiration is controlled by central pattern generating circuits in the brain stem, whose activity can be modulated by inputs from other brain areas to adapt respiration to autonomic and behavioral demands. The cerebellum is known to be part of the neuronal circuitry activated during respiratory challenges, such as hunger for air, but has not been found to be involved in the control of unobstructed breathing at rest (eupnea). Here we applied a measure of intrinsic rhythmicity, the CV2, which evaluates the similarity of subsequent intervals and is thus sensitive to changes in rhythmicity at the temporal resolution of individual respiratory intervals. The variability of intrinsic respiratory rhythmicity was reduced in a mouse model of cerebellar ataxia compared to their healthy littermates. Irrespective of that difference, the average respiratory rate and the average coefficient of variation (CV) were comparable between healthy and ataxic mice. We argue that these findings are consistent with a proposed role of the cerebellum in the coordination of respiration with other rhythmic orofacial movements, such as fluid licking and swallowing.

animal behavior and cognition↗

bioRxiv2019

Motor fatigability as evoked by repetitive movements results from a gradual breakdown of surround inhibition

Motor fatigability emerges when demanding tasks are executed over an extended period of time. Here, we used repetitive low-force movements that cause a gradual reduction in movement speed (or \"motor slowing\") to study the central component of fatigability in healthy adults. We show that motor slowing is associated with a gradual increase of net excitability in the motor network and, specifically, in primary motor cortex (M1), which results from overall disinhibition. Importantly, we link performance decrements to a breakdown of surround inhibition in M1, which is associated with high coactivation of antagonistic muscle groups. This is consistent with the model that a loss of inhibitory control might broaden the tuning of population vectors such that movement patterns become more variable, ill-timed and effortful. We propose that the release of inhibition in M1 is an important mechanism underpinning motor fatigability and, potentially, also pathological fatigue as frequently observed in patients with brain disorders.

neuroscience↗

bioRxiv2019

Infection triggers tumor regression through activation of innate immunity in Drosophila

The pioneering work of Dr. William Coley has shown that infections can stimulate the immune system and improve tumor growth control. However, the immune mechanisms responsible for the protective role of infectious agents have still not been identified. Here, we investigated the role of innate immune pathways in tumor regression by performing experimental infections in genetically modified Drosophila that develop invasive neoplastic tumors. After quantifying tumor size, through image processing, and immune gene expression with transcriptomic analyses, we analyzed the link between tumor size and pathogen-induced immune responses thanks to a combination of statistical and mathematical modeling. Drosophila larvae infected with a naturally-occurring bacterium showed a smaller tumor size compared to controls and fungus-infected larvae, thanks to an increase expression of Imd and Toll pathways. Our mathematical model reinforces this idea by showing that repeated acute infection could results in an even higher decrease in tumor size. Thus, our study suggests that infectious agents can induce tumor regression through the alteration of innate immune responses. This phenomenon, currently neglected in oncology, could have major implications for the elaboration of new preventive and immunotherapeutic strategies. One Sentence SummaryBacterial infections can decrease cancer cell accumulation through stimulation of innate immune responses.

immunology↗