Biology subjects

Chen, A.

Publications and source records attributed to Chen, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Linking land-use change, water quality, and host-parasite dynamics with droplet digital PCR and Bayesian path analyses

Global changes in land use and nutrient cycling are transforming ecosystems at unprecedented rates, with significant consequences for infectious disease dynamics. Aquatic environments are particularly vulnerable because the interplay of habitat modification, nutrient enrichment, and biodiversity loss can drive pronounced changes in the community composition of food webs, including hosts and parasites. Yet, despite well-documented effects of habitat modification on aquatic communities and food webs, the mechanisms through which these changes influence infectious disease dynamics remain poorly resolved. This gap arises, in part, because it remains challenging to disentangle how multiple stressors interact to shape disease outcomes and quantify parasite levels and host densities from field-collected samples. Here, we illustrate two tools that might help address these challenges. First, highly sensitive droplet digital PCR can quantify infection loads even when the signal:noise ratio is low. Second, stepwise Bayesian path analyses can identify the direct and indirect pathways connecting land-use changes to infectious disease dynamics. As a case study, we examined cyclopoid copepods and their helminth parasite, Schistocephalus solidus, across 47 freshwater lakes on Vancouver Island, a region strongly shaped by commercial logging, including widespread clear-cutting of old-growth forests. Our results reveal a positive correlation between copepod density and deforestation, potentially mediated by associated changes in water quality and calanoid copepods, key competitors of the focal host. ddPCR enabled sensitive detection of extremely low parasite signals in field-collected copepods. We detected positive infections in only 19.5% of the lakes surveyed, highlighting the difficulty of assessing disease dynamics in natural populations. Nonetheless, this study highlights the challenges of linking land-use change to disease outcomes, while also demonstrating that sensitive molecular and statistical tools offer new ways to reveal these hidden connections.

ecology↗

bioRxiv2026

A Multi-Scale Ecological Approach to Assessing Antimicrobial Resistance in a Freshwater Fish

Antimicrobial resistance (AMR) genes are increasingly recognized as an emerging environmental contaminant. Yet, the ecological mechanisms shaping their distribution across natural landscapes remain poorly understood. Here, we quantified AMR gene abundances in microbial communities sampled from wild fish from eight freshwater lakes on Vancouver Island and paired these gene-level measurements with fine-scale limnological and land-use data. Using droplet digital PCR, field surveys, and an iterative spatial forecasting framework that integrates Random Forest models with regression kriging, we explored how watershed-scale processes relate to variation in AMR genes across lakes. Our analyses reveal potential associations between elevated AMR gene levels, changes in water quality, deforestation, and geographic proximity to salmon aquaculture. By integrating data across biological and spatial scales, from genes within microbial communities to lake-level conditions and landscape patterns, this study illustrates the value of combining quantitative molecular measurements with geospatial modeling to identify environmental factors that may promote antimicrobial resistance in natural systems. Our approach provides a proof-of-concept and a general predictive framework for generating hypotheses and informing future monitoring efforts aimed at understanding, managing, and forecasting environmental reservoirs of resistance. SignificanceAntimicrobial resistance (AMR) genes are ancient components of environmental microbiomes. Yet, the mechanisms that generate modern hotspots of resistance across natural landscapes remain unclear. Here, we reveal how watershed-scale environmental change, including water quality metrics linked with deforestation and proximity to salmon aquaculture, predicts elevated AMR gene levels in the microbiomes of wild fish populations. By combining quantitative droplet digital PCR with ecological data and geospatial modeling, we move beyond isolated surveillance data to identify ecological mechanisms that promote antimicrobial resistance in freshwater ecosystems. This integrative approach provides mechanistic insight into why certain habitats, and the organisms within them, become reservoirs of resistance while others do not. Our findings highlight the importance of ecological context in understanding resistance evolution and offer a predictive tool for informing proactive monitoring and management strategies.

ecology↗

bioRxiv2026

spatiAlytica: Viewer-Grounded Multimodal Agentic System for Interactive Spatial Omics Analysis

Spatial transcriptomics and proteomics map tissue architecture and cellular interactions, but analysis remains limited by programming demands and text-centered AI agents that lack viewer grounding and cross-turn context. We present spatiAlytica, a viewer-centric multimodal interactive agentic system embedded in the Napari viewer that enables non-programmer biologists to perform iterative, hypothesis-driven spatial omics analysis via natural language. spatiAlytica couples viewer-state serialization, agentic memory, biological concept-to-data-field mapping, code generation and debugging, Spatial VQA, and grounded interpretation to support an exploratory analysis and interpretive reasoning workflow. We introduce spatiAlyticaBench, a comprehensive benchmark spanning 222 single-turn spatial analytical coding questions, 178 multi-turn sequential workflow questions, and 7,350 image-grounded reasoning questions. spatiAlytica outperformed strong agentic baselines, while using less time and tokens. Case studies across Kaposis sarcoma, colorectal cancer, and ovarian cancer recapitulated known spatial patterns and uncovered progressive CD8 T-cell dysfunction during KS progression.

bioinformatics↗

bioRxiv2026

Greater hypoxic burden predicts weaker gray matter-CSF coordination independent of non-hypoxic arousals: Implications for glymphatic activity

Study ObjectivesObstructive sleep apnea (OSA) is a risk factor for neurodegeneration, and glymphatic impairment may be one mechanistic pathway. Anti-phase coordination between brain pulsations and CSF flow, reflecting compensatory CSF displacement during each vascular pulsation cycle, supports glymphatic activity. This study examined whether hypoxic burden and sleep fragmentation, two distinct OSA pathologies, are differentially associated with brain pulsation-CSF flow dynamics. MethodsThis cross-sectional study included 28 individuals with newly identified OSA and 8 without OSA. Participants completed in-lab polysomnography or WatchPAT testing, providing measures of hypoxic burden, quantified as time below 90% oxygen saturation (T90), and non-hypoxic sleep fragmentation, quantified as respiratory effort-related arousals (RERAs). Participants also completed 7T resting-state functional MRI to estimate global BOLD-CSF, defined as anti-phase cross-correlation between blood-oxygen-level-dependent (BOLD) signal and CSF inflow. Associations were examined using correlation and hierarchical regression. Exploratory analyses examined region-specific BOLD-CSF and brain pulsation strength, quantified as BOLD amplitude. ResultsGreater T90 was associated with weaker global BOLD-CSF, independent of RERAs and covariates ({beta}=0.08,p=0.03). Greater T90 was also associated with higher BOLD amplitude across temporal, frontal, and parietal regions, but this elevation in amplitude was not accompanied by stronger region-specific BOLD-CSF coupling ({beta}=0.001,p>0.05). In contrast, among regions where BOLD amplitude was not associated with T90, greater BOLD amplitude predicted stronger region-specific BOLD-CSF ({beta}=-0.004,p<0.001). RERAs were not associated with global BOLD-CSF or BOLD amplitude. ConclusionsIn OSA, hypoxic burden may be the primary feature associated with impaired brain pulsation and CSF dynamics that support glymphatic activity. These alterations may be pronounced in the temporal lobe, where elevated pulsations were uncoupled from compensatory CSF displacement.

neuroscience↗

bioRxiv2026

Constitutive and inducible fibrosis explain immune variation among threespine stickleback populations

Understanding how immune variation arises in natural populations requires disentangling the relative contributions of host genetic differences, environmental variation, and parasite effects, which is rarely possible in wild systems. Threespine stickleback populations vary in their use of intraperitoneal fibrosis as a defense against the helminth parasite Schistocephalus solidus, providing a natural system to study the genetic and ecological drivers of immune variation. We combined a 46-lake field survey with common garden experiments on 20 representative populations exposed to multiple parasite genotypes to test whether population differences in fibrosis persist under controlled conditions and whether they depend on parasite genotype or lake ecology. Fibrosis variation was strongly heritable, with both constitutive and inducible components persisting under common garden conditions. In contrast, parasite genotype had only a weak effect on fibrosis responses. Moreover, inducible fibrosis covaried with lake environmental conditions, with populations from more eutrophic-like lakes exhibiting stronger responses than those from more oligotrophic-like lakes. Together, these results reveal ecologically structured divergence in heritable immune responses among natural populations.

evolutionary biology↗

bioRxiv2026

Exposure of Men to PTSD-Promoting Trauma Elevates Levels of Sperm miRNAs with Anxiety and Depression-Inducing Activities

Chronically stressing male rodents can induce stress-specific epigenetic changes in sperm that contribute to altered offspring phenotypes. Whether similar phenomena occur in men is unclear. This study addresses this knowledge gap by analyzing sperm microRNAs (miRNAs) from 51 men exposed to various levels of adult trauma including crime, disaster, and physical or sexual violence, quantified by the Trauma History Questionnaire (THQ), a measure of risk for Post-Traumatic Stress Disorder (PTSD). Four sperm miRNAs, miR-532-3p, 491-5p, 375-3p and 361-3p correlated positively with mens THQ scores, showing 4X to 130X over expression in sperm from the most highly traumatized men. These changes were independent of mens adverse childhood experiences (ACEs), which we previously linked to decreased miR-34/449 in their sperm; and sperm miR-34/449 levels were not associated with THQ scores. Injecting these 4 miRNAs into fertilized mouse oocytes at levels comparable to those found in men reporting high THQ scores yielded offspring with elevated anxiety-and depression-like phenotypes. This finding differs from the stress related phenotypes we observed in offspring of mice fertilized by sperm with reduced levels of miR-34/449. Consistent with only a small subset of men with high THQ scores developing PTSD, we observed no statistically significant increase in overall anxiety or depression among this highly traumatized group, however there were indications of increased sleeplessness, appetite and concentration difficulties and negative self-concept among this group. Nevertheless, almost all men reporting high THQ scores had elevated levels of all 4 of these miRNAs in their sperm, suggesting these trauma-induced epigenetic changes may raise mental health risks in the offspring of men with only subtle mental health problems. Since [~]20 % of men report either THQ or ACE scores in the ranges linked here and in our earlier study to changes in sperm miRNAs that in mice lead to elevated levels of stress-related behaviors, a large human population with an elevated risk of transmitting stress-related traits to their offspring likely exists.

genetics↗

bioRxiv2026

A broad-host-range Rhizobium rhizogenes strain enables transient expression across diverse crops and establishes functional assays in faba bean

Agrobacterium-mediated transient expression has revolutionized plant research, enabling numerous landmark discoveries across diverse areas of plant biology. Yet this powerful approach remains largely confined to solanaceous species, leaving most economically important crop families without a comparable rapid assay platform. Here, we show that an engineered Rhizobium rhizogenes strain, AS109, mediates efficient transient expression across diverse dicot species spanning multiple taxonomic families, consistently outperforming commonly used laboratory agrobacterial strains. Leveraging the broad host range of AS109, we establish a suite of functional assays in faba bean (Vicia faba), including protein localisation, RNA interference-mediated gene silencing, cell-surface elicitor recognition screens, nucleotide-binding leucine-rich repeat receptor (NLR) activation, and infection cell biology at the host-pathogen interface. We further demonstrate that both singleton NLRs and sensor-helper NLR pairs from Solanaceae retain effector recognition and cell death activity when transferred into faba bean, establishing a rapid platform for evaluating cross-family transferability of disease-resistance genes. AS109 thus provides an accessible and versatile chassis for functional genomics in non-model crops, bridging the widening gap between hypothesis generation and experimental validation across diverse plant species.

plant biology↗

bioRxiv2026

The Effects of Phosphorylation on the Structure and Function of Motif A, an Intrinsically Disordered Region within SIRT1

The NAD+ dependent deacetylase sirtuin-1 (SIRT1) is known to elicit cellular defenses against aging, cancer, and other aberrant pathologies. Previous studies have identified an intrinsically disordered region of SIRT1 comprised of N-terminal residues 1-52, herein referred to as motif A, which activates SIRT1 activity, likely through intramolecular interactions. Additionally, phosphorylation of N-terminal residues Ser27 and Ser47 has been shown to be important for regulating SIRT1 activity and stability. The lack of in vitro characterization of these effects hampers our further understanding of the role of motif A in SIRT1 regulation. In this study, we elucidate the role phosphorylation plays in motif As structure as well as its regulatory effects on SIRT1 activity against Ac-p65. We find that phosphomimetic mutation at Ser27 significantly increases the activation effect of motif A towards SIRT1. This result is supported by molecular dynamics simulations of the phosphomimetics, which reveal stabilization of different transient structures for motif A depending on whether Ser27 and Ser47 have been modified. A key finding suggested by this study is that phosphorylation of S27 appears to activate SIRT1 by causing motif A, which is intrinsically disordered in the WT, to fold into an ordered structure. This conclusion is based on both the experimental findings and simulation results. These findings contribute to our understanding of SIRT1 regulation, specifically the role played by phosphorylation within the N-terminal disordered region.

biochemistry↗

bioRxiv2026

Decoding concept representations in aphasia after stroke

Many stroke survivors with aphasia struggle to map their thoughts into words or motor plans. Neuroprostheses that decode concept representations could help these individuals communicate by predicting the words, phrases, or sentences that they are struggling to produce. Here we decoded concept representations measured using functional magnetic resonance imaging (fMRI) from participants with different aphasia profiles. The decoders generated continuous word sequences that could describe the concepts that the participants were hearing about, seeing, or imagining. To forecast how this approach would generalize across the heterogeneity of aphasia profiles, we characterized how stroke affects the anatomical organization and information capacity of conceptual processing. Mapping how concepts are organized across the brain, we found that conceptual tuning during non-linguistic processing was largely consistent between the participants with aphasia and neurologically healthy participants. Comparing information processing between the participants with aphasia and neurologically healthy participants, we found that both groups processed similar amounts of non-linguistic information. Our findings indicate that concept representations can be largely spared in individuals with aphasia and demonstrate how these representations can be decoded to support communication.

neuroscience↗

bioRxiv2026

Beyond the mean: genetic control of gene expression fidelity and dispersion

For decades, molecular biologists have interpreted gene regulation through measurements of mean gene expression, because they could not resolve regulatory variation among individual cells. The advent of single-cell genomics has now made that variation measurable, revealing pervasive differences in gene expression among apparently similar cells. Whether this variation mainly reflects stochastic noise or an informative regulatory property remains unclear. Here we show that mean-corrected gene expression dispersion is a reproducible and biologically structured feature of gene regulation that reflects regulatory fidelity. In heterogeneous differentiated cardiac cultures, genes with low dispersion are shared across cell types, enriched for housekeeping functions, depleted for expression quantitative trait loci, and more highly connected in transcriptional and protein interaction networks. In a comparative single-cell system spanning human, chimpanzee, and allotetraploid cells, a substantial subset of interspecies differences in regulatory dispersion persists in a shared trans environment, indicating that gene expression fidelity is often regulated in cis. Our findings establish gene expression dispersion as a genetically encoded dimension of gene regulation that is distinct from mean expression, and places dispersion along a fidelity-plasticity axis with implications for development, disease, and threshold-dependent cellular phenotypes.

genomics↗

bioRxiv2026

MINGL Quantifies Borders, Gradients, and Heterogeneity in Multicellular Tissue Organization

Tissues are organized with interacting multicellular organizational units whose interfaces and transitions shape function in health and disease. Current spatial-omics analyses typically assign cells to a single cellular neighborhood--ignoring natural gradients, heterogeneity, and borders. Here we present MINGL (Mixture-based Identification of Neighborhood Gradients with Likelihood estimates), a probabilistic framework that converts existing neighborhood annotations into continuous measures of tissue architecture. MINGL models each cell by multi-membership probabilities across hierarchical organizational units and uses these probabilities to identify enriched cells at interfaces between units, constructs interaction networks across hierarchical scales, quantifies compositional gradient transitions, measures context-specific composition heterogeneity, and provides a starting point for neighborhood resolution. Across multiple spatial-omic datasets spanning melanoma, healthy intestine, and Barretts Esophagus progression, MINGL detected innate immune-enriched interfaces at tumor and anatomical interfaces, plasma cell niches linking cellular neighborhoods, distinct regimes of sharp and gradual transitions between organizational states, and disease-associated neighborhood remodeling. By treating neighborhood assignment uncertainty as a biological signal rather than noise, MINGL unifies discrete and continuous representations of tissue organization and makes tissue architecture measurable, comparable, and scalable across biological scales and spatial-omics platforms.

systems biology↗

bioRxiv2026

Acid stress modulates metabolo-inflammatory pathways in oral epithelial cells

Acidification of the oral environment has been implicated in the initiation and progression of oral pathologies including oral cancer, but how acidic environments modulate normal oral epithelial cell (OEC) responses to microbial ligands is not understood. This study examined the impact of acidic stress on OEC morphological, molecular, and functional responses to toll-like-receptor ligand engagement in vitro. OEC cultures were exposed to either normal (pH:=:8.0) or acidified growth media (pH:=:3.0) for 24 hours prior to machine-learning-guided morphological analysis and exposure to either toll-like receptor (TLR)5 (flagellin) or TLR2/TLR1 (Pam3CSK4) agonists. Multiplex gene expression technology was used to quantify the transcriptional responses of metabolic-and immune-related genes at 6 hours post-TLR agonist exposure. OEC-mediated production of transforming growth factor-beta (TGF-{beta}) was assessed by enzyme-linked immunosorbent assay at 2-, 6-, and 24-hours post-agonist exposure. Results showed that acid exposure induced significant changes to OEC morphology resembling epithelial-mesenchymal transition, the differential expression of n=197 metabolic-and n=43 immune-related genes and significantly increased OEC TGF-{beta}1 production. The results demonstrate that acid stress skews normal OECs towards pro-inflammatory and pro-oncogenic phenotypes when faced with concomitant microbial ligand challenge and provide key molecular clues to OEC survival strategies with potential implications for elucidating the early molecular events in the development of epithelial dysplasia. Article HighlightsO_LIAcute acid exposure reduces survival of OECs C_LIO_LIA subpopulation of OECs is resistant to acid-mediated cell loss and undergo morphometric changes consistent with epithelial-mesenchymal transition C_LIO_LIConcurrent acid stress and TLR stimulation modulates transcription of immune and metabolic genes in OECs C_LIO_LIAcid stress increases TGF-{beta}1 protein production of OECs following TLR agonist stimulation C_LI

cell biology↗

bioRxiv2026

A universal platform for simultaneous TCRα/β removal enables safer and more potent TCR therapies and autoimmune modeling

Adoptive T-cell therapies using tumour-specific T-cell receptors (TCRs) are limited by competition with endogenous receptors, which impairs efficacy and poses risks of off-target autoreactivity. Here we present a CRISPR-based platform that completely and selectively eliminates both endogenous TCR- and -{beta} chains without affecting introduced transgenic TCRs, irrespective of codon optimization. This approach achieves >90% deletion efficiency in Jurkat and primary human T cells, markedly enhancing the expression, pairing fidelity, and functional potency of transgenic receptors. Using a clinically relevant HLA-A*02:01-restricted DMF5 TCR, we show that dual TCR ablation boosts antigen-specific activation and cytotoxicity in vitro and significantly enhances tumor clearance in vivo in human immune system (HIS) mice, while preventing graft-versus-host disease (GVHD). Targeted locus amplification revealed that CRISPR-induced double-strand breaks did not alter lentiviral integration profiles, confirming genomic safety. Extending this approach to four insulin-reactive TCRs demonstrated that removal of endogenous receptors increased transduction efficiency and functional activity, with one (1E6) showing selective activation and infiltration of stem cell-derived islet grafts (SC-islets) in vivo. This study establishes a universal, safe, and scalable genome-editing platform for generating functionally precise human T cells. By integrating cancer immunotherapy and autoimmune disease modelling within a single framework, it provides a strong preclinical rationale for dual endogenous TCR removal as a route to improved specificity, safety, and therapeutic efficacy in TCR-based cell therapies.

immunology↗

bioRxiv2026

Uncovering Conceptual Biases in DNA Stabilization: A Student-Led Investigation

Deoxyribonucleic acid (DNA) stands as one of the most foundational concepts in life sciences, essential for students to master. However, when surveyed about the forces that stabilize the double-stranded DNA structure, many students exhibited a conceptual bias-- favoring base pairing as the primary stabilizing force, while overlooking the equally critical role of base stacking interactions. To investigate the origins of this misconception, students conducted a comprehensive analysis of 35 widely used textbooks. Their findings revealed that one-third of these texts explicitly emphasized base pairing as the sole stabilizing force in their written content. Furthermore, two-thirds of the textbook contained illustrations that reinforced this bias, visually highlighting base pairing while neglecting base stacking. Recognizing this bias, students embarked on a literature review to gain a more accurate and nuanced understanding of DNA stabilization. Through this research, we identified three concept areas--DNA structure and function, environmental effects on DNA, and DNA-protein interactions--to illustrate how base pairing and base stacking work in concert to stabilize the antiparallel double helical structure of DNA. This interplay between base pairing and base stacking is crucial not only for the structural integrity of DNA, but also for its biological functionality. By addressing this conceptual bias, we aim to promote a more balanced and scientifically accurate representation of DNA stabilization in educational materials.

scientific communication and education↗

bioRxiv2026

Metabolic plasticity of sphingolipids governs cancer cell fitness in acidic tumor ecosystems

Cell state plasticity enables cancer cells to rapidly adapt to fluctuating microenvironments without requiring genetic alteration, shaping tumor evolution under stress. Extracellular acidosis is a persistent feature of solid tumors that impose strong selective pressure, yet how cancer cells maintain fitness under acute and chronic acidic conditions remains unclear. Here, we show that adaptation to acidosis is mediated by plastic rewiring of sphingolipid metabolism centered on ceramide turnover. Spatial multi-omics analysis of three-dimensional tumor models revealed enrichment of ceramides within acidic niches, consistent with a stress-induced phenotype. While acute acidosis promoted ceramide accumulation and reduced fitness, chronic exposure selected for cells capable of dynamically redistributing sphingolipid flux across multiple clearance pathways. Functional perturbation demonstrated that inhibition of individual pathways was insufficient to compromise survival, whereas simultaneous disruption of all ceramide clearance routes resulted in cell death, revealing a degenerate metabolic architecture. This network-level flexibility enables cancer cells to maintain fitness by switching between alternative metabolic states under acidic stress. Together, our findings identify sphingolipid metabolic plasticity as an adaptive strategy that supports tumor persistence in acidic ecosystems and suggest that targeting metabolic flexibility, rather than individual pathways, may provide a more effective therapeutic approach.

cancer biology↗

bioRxiv2026

A plug-and-play ROI imaging module and deep-learning denoising framework extend three-photon microscopy to 1.7 mm depth

Three-photon microscopy (3PM) has extended optical imaging beyond the reach of two-photon microscopy (2PM), but its practical depth remains far below theoretical predictions because of low photon efficiency and severe noise contamination. Here we present an integrated hardware and software solution that addresses these limitations. We developed a plug-and-play region-of-interest (ROI) imaging module that selectively excites neuron-occupied regions to improve power efficiency and reduce photothermal stress. The module incorporates frame-partitioned accumulative (FPA) imaging for high signal-to-noise ratio (SNR) structural acquisition, automated neuron segmentation, and motion-robust registration for stable recordings. Complementing this, OptiCal is a cascaded deep-learning framework that removes mixed noise including periodic, motion-induced, and random components. Together, these innovations enable high-fidelity imaging to 1.7 mm depth, extending the practical limit of 3PM by about 400 {micro}m while maintaining low excitation power. Our results reveal reliable calcium activity and behavior-correlated dynamics in deep medial prefrontal cortex of awake mice.

neuroscience↗

bioRxiv2025

Pharmacological Inhibition of FKBP51 Mitigates Early Life Adversity-Induced Social Deficits

Early life adversity (ELA) is a major risk factor for psychiatric disorders, but targeted preventative strategies are lacking due to poor mechanistic insight. The FKBP51 protein, a co-chaperone of the glucocorticoid receptor, is a key mediator of stress vulnerability. We tested if pharmacological inhibition of FKBP51 with the selective inhibitor SAFit2 prevents the long-term consequences of ELA. Mice exposed to ELA exhibited persistent deficits in social behavior, manifesting as social subordination in adolescence and adulthood. Early-life SAFit2 treatment fully rescued these ELA-induced behavioral impairments. Transcriptional profiling across six stress-relevant brain regions revealed that SAFit2 normalized ELA-driven gene expression changes, particularly in the medial prefrontal cortex and nucleus accumbens. Functional analysis showed the rescue converged on immunoregulatory and neuroactive ligand-receptor signaling pathways. Our findings establish FKBP51 as a critical pharmacological target for reversing the lasting impact of early life adversity on brain function, offering a path toward preventative treatment for ELA-related psychopathology.

neuroscience↗

bioRxiv2025

Metabolic medications modify prostate cancer progression through exosome reprogramming

Among prostate cancer patients, co-morbid Type 2 Diabetes (T2D) is associated with faster progression to biochemical recurrence and increased risk of mortality. Previous work from our lab provides evidence that exosomes purified from media of insulin resistant adipocytes or T2D patient plasma likely drives these outcomes by delivering miRNAs that exacerbate tumor aggressiveness in several breast and prostate cancer models. Here, we build on our previous findings to investigate whether treatment with metabolic medications attenuates the tumor promoting effects of exosomes. We found that human DU145 cells, a model for prostate cancer, treated with plasma exosomes from T2D patients, shows patterns in global gene transcription that resolve by patient treatment with metformin. To test the effects of metformin experimentally, we used a murine model of insulin resistance (IR). Treating DU145 cells with miRNAs purified from the plasma exosomes of IR mice, we found that cells transfected with miRNAs from the metformin-treated IR group displayed significantly less migration than cells transfected with miRNAs from the unmedicated IR group. We suggest that metformin may partially reverse effects of T2D to exacerbate tumor aggressiveness by modifying the miRNA payload of plasma exosomes.

cancer biology↗