Biology subjects

Xi, Y.

Publications and source records attributed to Xi, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

miRAssist: a context-aware, evidence integration framework for interpretable miRNA-target prioritization

Motivation: MicroRNA-target interaction prediction remains challenging because many existing tools provide prediction scores or ranked candidate lists without making the supporting evidence easy to interpret or relate to a specific biological context. Results: Here, we developed miRAssist, a context-aware evidence-integration framework for interpretable miRNA-target prioritization. miRAssist integrates six evidence families, including sequence complementarity, thermodynamic stability, sequence conservation, target-site accessibility, functional binding, and functional repression. A sequence-defined candidate universe was generated, resulting in 280,917 candidate interactions. Using miRTarBase-supported interactions as known-positive labels, six supervised scoring approaches were evaluated using a grouped train/test split by miRNA. Random forest showed the strongest performance and was selected. miRAssist also produced stronger known-positive enrichment than established miRNA-target prediction models in the evaluated benchmark. An LLM-assisted interface further supports natural-language database querying and evidence-grounded summarization of prioritized candidates.

bioinformatics↗

bioRxiv2026

The filopodial scaffold polyphosphate dictates cell adhesion-versus-invasion decisions

Inorganic polyphosphate (polyP) is an ancient polymer conserved across all life, serving cell type and location specific functions in every major compartment. Yet its role at the plasma membrane, where it accumulates to peak levels in many primary cells, is largely unknown. Here we identify polyP as a stabilizing component of filopodia, actin based membrane protrusions that govern cell adhesion, contact inhibition, and chemotaxis. Elevating cellular polyP increases filopodial stability and enhances cell adhesion, whereas reducing polyP accelerates filopodial disassembly and promotes cell migration. Mechanistically, we find that polyP acts as a structural filopodial scaffold, recruiting and organizing IRSp53, a membrane curvature inducing protein. We show that metastatic fibroblasts and breast cancer organoids carry markedly reduced and intracellularly reorganized polyP levels relative to their non transformed counterparts. Restoring endogenous polyP via lipid nanoparticle delivery suppresses their invasive phenotypes and reverses prometastatic gene expression signatures, implicating polyP as a primordial tumor suppressor.

cell biology↗

bioRxiv2026

Computational design of de novo integrated domains enables rational control of pathogen effector recognition in plant NLR immune receptors.

The rapid evolution of plant pathogens poses a persistent threat to global agricultural sustainability, often outpacing the discovery and deployment of natural disease resistance genes. While bioengineering of plant intracellular immune receptors (NLRs) offers a potential solution, developing bespoke immune recognition remains constrained by the laborious characterisation of natural receptors and plant-pathogen interactions. Here, we describe a programmable framework that leverages generative AI protein design tools, RFdiffusion and ProteinMPNN, to design de novo integrated domains (IDs) against diverse pathogen effectors. By integrating these bespoke binders into the modular rice blast Pik-1/Pik-2 NLR receptor chassis, we successfully engineer recognition of a non-cognate virulence factor (effector) from the Panama disease pathogen, Fusarium oxysporum f. sp. cubense Tropical Race 4. Functional assays in Nicotiana benthamiana demonstrate that these de novo domains facilitate specific effector perception and initiate immune signalling, while structural and biophysical analyses confirm that de novo integrated domains maintain high structural fidelity to the initial designs and associate with their targets via the predicted interaction interfaces. Additionally, our findings provide orthogonal evidence for the role of integrated domains in regulation of NLR signalling, demonstrating integration of de novo IDs can either trigger autoactivity or, in some cases, lead to effector-mediated repression of cell death. By decoupling immune perception from natural evolutionary history through deploying AI-designed sensory domains, this work establishes a design-lead framework for generation of programmable plant immune receptors, providing a new avenue for bioengineering crops against emerging pathogens.

plant biology↗

bioRxiv2026

Somatosensory gating dysfunction is masked by cognitive variability in cognitively impaired individuals

Disruptions in somatosensory processing have been observed in cognitive impairment (CI), suggesting that alterations in sensory processing may emerge earlier during cognitive decline than previously recognized. Somatosensory gating (SG) is an automatic inhibitory mechanism that protects neural resources by suppressing responses to redundant, non-behaviorally relevant stimuli. Prior work has demonstrated exaggerated gamma SG and response amplitudes in the primary somatosensory cortex (S1) of individuals with Alzheimers disease-confirmed pathology, and these effects were masked by variability in attention/executive function performance. However, whether similar relationships are present during earlier stages of cognitive decline, such as CI, remains unclear. Herein, 63 cognitively healthy older adults (CH; mean age = 59.9 {+/-} 8.6 years) and 32 individuals with CI (mean age = 62.4 {+/-} 8.8 years) underwent magnetoencephalography (MEG) while completing a paired-pulse SG paradigm designed to probe inhibitory sensory processing. MEG oscillatory responses were source-imaged using a beamformer. Time series data were extracted from the peak voxel to quantify oscillatory dynamics and SG. Neuropsychological testing was conducted to assess attention/executive function. After controlling for attention/executive function variance, exaggerated gamma SG was observed in adults with CI compared with CH adults (p < 0.05). Additionally, adults with CI exhibited increased beta peak frequency following the second stimulation (p < 0.01) and a group-by-age interaction for theta SG in S1 (p < 0.05). Together, these results suggest somatosensory abnormalities are present in earlier stages of cognitive decline and highlight a dynamic interaction between sensory processing and cognitive systems during this decline.

neuroscience↗

bioRxiv2026

Reduced Somatosensory Oscillatory Dynamics and Inhibition in Moderate-to-Severe Nociceptive Pain

Nociceptive pain is the most common pain condition, and moderate-to-severe nociceptive pain substantially impacts daily functioning, constituting a significant public health burden. Despite this, most studies investigating the neural mechanisms underlying somatosensory processing and inhibition have focused on other pain conditions (e.g., neuropathic, nociplastic, or mixed pain). Thus, the extent to which neural aberrancies detected in these other populations extend to or differentiate from nociceptive pain conditions remains largely unknown. In this study, 29 individuals with moderate-to-severe nociceptive pain (MSNP) and 47 pain-free (PF) controls underwent magnetoencephalography (MEG) alongside a paired-pulse somatosensory stimulation paradigm to examine somatosensory cortical processing and functional inhibition. Pain status and intensity were determined using validated pain questionnaires, painDETECT and PROMIS-29, respectively. MEG oscillatory responses were source localized via a beamformer to the primary somatosensory cortex (S1) and time series data were extracted from the peak voxel to quantify the dynamics of somatosensory gating (SG; index of cortical inhibitory processing), oscillatory response power, and spontaneous power. We found that adults with MSNP exhibit aberrant theta SG in contralateral S1 compared to PF controls, reflecting reduced functional inhibition of innocuous stimulus processing in this region. Additionally, individuals with MSNP demonstrated exaggerated gamma responses but blunted alpha responses in contralateral S1 to innocuous stimulation. Finally, individuals with MSNP were characterized by weaker spontaneous alpha in contralateral S1 that scaled with self-reported pain intensity. Together, these findings suggest that experiencing MSNP is associated with disrupted somatosensory and cortical inhibitory processing.

neuroscience↗

bioRxiv2026

Age-Related Alterations in Multispectral Somatosensory Gating: Evidence for Partial Compensation in Attentional Performance

Healthy cognitive aging involves selective changes, with relative preservation of some domains and decline in others, particularly attention, inhibitory control, and executive function. Somatosensory gating (SG) refers to the brains ability to suppress neural responses to redundant tactile input, conserving resources for relevant stimuli and reflects pre-attentive and inhibitory mechanisms. Prior region-of-interest studies have shown age-related reductions in gamma SG within contralateral primary somatosensory cortex (S1), and modulation of theta, alpha, and beta SG by attention in young adults. However, whole-brain, multispectral age effects remain unclear. In this study, 63 middle-to-older aged adults (38 females; mean age = 59.9 {+/-} 8.6 years) underwent magnetoencephalography during a paired-pulse somatosensory paradigm. SG was quantified as attenuation of the neural response to the second stimulus relative to the first. Time-frequency analyses identified theta (4-7 Hz), alpha (8-13 Hz), beta (15-25 Hz), and gamma (30-90 Hz) oscillatory responses, and band-specific voxel-wise whole-brain gating maps assessed age-related effects. Attention/executive function was also measured. Results showed significant age-related increases in gamma SG in the contralateral supplementary motor area. Mediation analyses suggested this increase partially offsets age-related declines in attention/executive function, consistent with a partial compensatory mechanism. Additionally, theta SG in contralateral S1 increased with age. These findings demonstrate frequency- and region-specific age-related alterations in SG, suggesting that older adults may recruit enhanced inhibitory mechanisms, particularly in higher-order sensorimotor regions, to support cognitive function.

neuroscience↗

bioRxiv2026

METTL14-dependent m6A modification restrains interferon signaling to prevent myocarditis and dilated Cardiomyopathy

The impact of inflammation on heart failure is increasingly recognized; but how cardiomyocyte restrains innate immune activation remains poorly defined, and nor does the role of N-methyladenosine (mA) modification in maintaining cardiac immune homeostasis. Here, we demonstrate that cardiomyocyte-specific deletion of the mA methyltransferase METTL14 triggers myocarditis, dilated cardiomyopathy, and premature lethality. Meanwhile, widespread hypomethylation and upregulation of innate immune and necroptosis-related transcripts in Mettl14-deficient hearts exemplified by IFN-1 and STAT1. Mechanistically, METTL14 deficiency promotes RIPK1 accumulation thereby priming cardiomyocytes for necroptosis and inflammatory cell death. Genetic ablation of IFN-I receptor Ifnar1 can largely rescue the processes and improve cardiac function and survival. Furthermore, METTL14 loss disrupts mitochondrial integrity and autophagy/mitophagy flux, suggesting mitochondrial dysfunction-driven innate immune activation upstream of IFN-I signaling. Collectively, these findings identify METTL14-mediated mA modification as a critical safeguard against cardiomyocyte-intrinsic IFN-I signaling and necroptosis and establish an epitranscriptomic-innate immune axis that drives inflammatory heart failure.

pathology↗

bioRxiv2026

Sex-specific Genetic Regulatory Effects in Chickens

Sexual dimorphism is a defining vertebrate feature, yet its sex-specific molecular architecture remains poorly understood. Here we established a sex-balanced, uniformly reared chicken cohort to map this landscape, integrating individual whole-genome sequencing with 7,969 bulk and 779,380 single nucleus transcriptomes across 32 tissues from 280 birds. We identified 495,098 independent expression quantitative trait loci for 20,194 genes, including 10,937 loci modulated by cell-type composition. Notably, 340 genes were regulated by 449 loci in a sex-dependent manner, significantly enrichment in endocrine tissues like adipose and the adrenal gland. Furthermore, we fine-mapped 1,219 structural variants, demonstrating their unique roles to tissue- and sex-specific expression beyond SNPs. Ultimately, we showed the utility of these regulatory effects in elucidating the molecular basis of metabolism and complex traits in both chickens and humans. This comprehensive atlas of regulatory effects provides profound insights into the genomic and molecular basis of sexual dimorphism in vertebrates.

genomics↗

bioRxiv2026

MNRR1 is required for Triple Negative Breast Cancer growth and metastasis and can be targeted by repurposed drugs.

Despite progress in recent decades, breast cancers remain the most diagnosed malignancies, and second leading cause of cancer death, in women. Although improved screening and systemic and endocrine adjuvant approaches have contributed to major declines in breast cancer mortality, current standard of care drugs are extremely toxic, and many women continue to be overtreated. Although nearly two-thirds of breast cancers are hormone-responsive, aggressive subtypes, particularly Triple Negative Breast Cancer (TNBC), still lack safe oral medications. Recently the roles that mitochondria play in TNBC carcinogenesis, metastasis, and resistance to treatment have garnered a great deal of attention. Contrary to the popular dogma that cancer cells are powered by glycolysis, metastatic breast cancer cells have enhanced mitochondrial function. Our work identified that Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1; also, CHCHD2, PARK22), a key coordinator of mitochondrial-nuclear crosstalk that is physically present in both compartments, is overexpressed in TNBC cells and is an important regulator of metastasis signaling. We have identified Heat Shock Factor 1 (HSF1) as the main transcription factor that activates the MNRR1 promoter in TNBC cell lines. In the mitochondria, MNRR1 protein facilitates ATP production and inhibits apoptosis, whereas in the nucleus it regulates the transcription of stress-responsive genes including several required for epithelial to mesenchymal transition (EMT), metabolic flexibility, and cell growth. Thus, each of the bi-organellar functions of MNRR1 constitutes processes regarded as hallmarks of cancer. For reasons that are not yet fully understood, MNRR1 levels display a significant and robust ancestry bias, showing increased expression in tumor samples from Non-Hispanic Black (NHB) women when compared to disease-matched tumors from Non-Hispanic White (NHW) patients. It is possible that increased levels of MNRR1 may underlie the aggressive metastatic phenotype observed in many NHB patients. In further support of this observation, loss of MNRR1 function, either genetically or by use of inhibitors, reduces TNBC growth and metastasis. MNRR1 therefore is an attractive therapeutic target that could be exploited for design of novel therapies or as adjuncts to existing ones.

cancer biology↗

bioRxiv2026

IR-B deficiency and fatty acid dysregulation accelerate prostate cancer progression via PI3K/AKT signaling

The insulin receptor (IR) is markedly overexpressed in both human and mouse prostate cancer, with a significant elevation in the IR-A/IR-B ratio across patient tissues, cell lines, and Hi-Myc mouse prostates. To elucidate the role of IR-B in prostate tumorigenesis, we generated a prostate-specific IR-B knockout (KO) mouse model using Pbsn-Cre-driven recombination. Prostate-restricted loss of IR-B was confirmed at the transcript level and did not affect other tissues. Crossing these mice with Hi-Myc transgenics revealed that IR-B deficiency promotes accelerated progression to invasive adenocarcinoma, characterized by enhanced cellular proliferation and atypical histopathology. Transcriptomic and metabolomic profiling of dorsolateral prostate lobes demonstrated activation of PI3K/AKT and mTOR signaling, along with upregulation of IRS1/2/4 and IGF2. Metabolite analyses indicated elevated fatty acid levels and enhanced lipolysis pathways, implicating metabolic reprogramming in tumor progression. Notably, glucose and lipid metabolism genes, including GLUT1, GLUT12, FASN, and GPR120, were upregulated, accompanied by an increased BCL2/BAX ratio, suggesting apoptosis inhibition. Functional studies further revealed opposing roles of dietary fatty acids: {omega}-3 polyunsaturated fatty acids (EPA, DHA) suppressed prostate cancer cell survival, proliferation, and PI3K/AKT signaling while promoting apoptosis, whereas {omega}-6 fatty acid (arachidonic acid) exerted pro-tumorigenic, anti-apoptotic effects. Collectively, these findings identify IR-B loss as a driver of metabolic and signaling reprogramming that accelerates prostate tumorigenesis, while highlighting {omega}-3 fatty acids as potential modulators counteracting IR-B-deficient prostate cancer progression.

cancer biology↗

bioRxiv2025

Engineering a Multilayer Microfluidic Airway-On-A-Chip with Tunable GelMA Hydrogel for Physiologically Relevant Aerosol Exposure Studies

Climate change-driven increases in forest fires pose a major global health risk due to exposure to smoke containing hazardous gases and fine particulates, emphasizing the need for physiologically relevant in vitro airway models for studying smoke-induced responses. Microfluidic lung-on-a-chip technologies provide a strong foundation for in vitro airway modeling and ongoing developments are expanding their ability to incorporate multicellular organization, extracellular matrix complexity, and physiologically relevant exposure methods. This work presents the optimization and integration of a photopolymerizable gelatin methacrylate (GelMA)-based hydrogel into a microfluidic airway-on-a-chip that models the human small conducting airways and supports controlled aerosol exposure to wood smoke. The GelMA hydrogel was optimized to support fibroblast encapsulation, endothelial, and epithelial adhesion and robust mechanical stability. The device combines the hydrogel with a compartmentalized microchannel layout, and sacrificial molding to create a 3D organotypic airway culture featuring a multilayer architecture, 3D stromal matrix, and a perfusable vasculature-like lumen. Coupling the platform with a custom aerosol exposure system enables precise, biomimetic exposure to whole wood smoke. Proof-of-concept studies using transforming growth factor beta1 (TGF-{beta}1) and whole wood smoke elicited expected inflammatory and fibrotic responses, validating the platforms physiological relevance for inhalation studies and investigating smoke-induced airway remodeling and inflammation.

bioengineering↗

bioRxiv2025

YAP1 defines an emergent, plastic population of relapsed small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid onset of chemoresistance and poor clinical outcomes. Transcriptional heterogeneity among treatment-naive SCLC tumors underlies four transcriptional subtypes, each with distinct clinical vulnerabilities. Though previously hypothesized to delineate a distinct subtype, expression of YAP1 is largely absent from treatment-naive, pure SCLC. To characterize relapsed SCLC, circulating tumor DNA, circulating tumor cells, and core needle biopsies from SCLC patients and preclinical models following resistance to standard-of-care therapies were analyzed. In contrast to treatment-naive SCLC, these analyses reveal an emergent YAP1-positive cell population that coincides with treatment resistance. These YAP1-positive cells exhibit characteristics of drug tolerant persister cells, including senescence, stemness, and plasticity, as YAP1 positive cells largely abandon features characteristic of SCLC to adopt those of large-cell neuroendocrine carcinoma (LCNEC). As a result of this SCLC-like to LCNEC-like evolution, YAP1-positive cells lack several clinically relevant SCLC surface targets (i.e., DLL3, SEZ6), but are enriched for others (i.e., B7-H3, TROP2). We propose a model where YAP1 expressing cells emerge with SCLC treatment resistance and characterize a tenacious subpopulation capable of diverging from the treatment naive lineage and adopting features to evade therapeutic response.

cancer biology↗

bioRxiv2025

A multicenter spatial transcriptomics atlas of human tuberculosis and non-tuberculous mycobacterial disease

Granulomas are the hallmark of mycobacterial (MB) infections, forming structured immune environments that contain bacteria but also drive disease persistence. However, their spatial and functional organization remains unclear. Using spatial RNA sequencing on 38 patient samples, we identified five distinct granuloma niches: a necrotic core, an immune-activated inner niche, an inflammatory and an extracellular matrix (ECM)-remodeling middle niche, an outer structural niche, and a tertiary lymphoid structure niche supporting antigen presentation. Immune activity peaks in the inner niche, transitioning to fibrosis at the periphery. Lymph node granulomas display reduced fibroblast involvement but stronger JAK-STAT activation. Mycobacterium tuberculosis (MTB) granulomas exhibit heightened JAK-STAT and IFN-{gamma} signaling, while non-tuberculous mycobacteria (NTM) granulomas show increased hypoxia signatures. Compared to sarcoidosis, MB granulomas feature a structured adaptive immune response, marked by the clustering of plasma cells. Our findings, accessible via https://lab-li.ciim-hannover.de/mb-granuloma/, define key disease signatures, guiding biomarker discovery and therapeutic targeting in granuloma-related diseases.

bioinformatics↗

bioRxiv2025

Cytoplasmic Abundant Heat-Soluble Proteins from Tardigrades Protect Synthetic Cells Under Stress

Cytoplasmic abundant heat-soluble (CAHS) proteins, a stress-responsive intrinsically disordered protein from tardigrades, have been discovered to form gel-like networks providing structural support during dehydration, thus enabling anhydrobiosis. However, the mechanism by which CAHS proteins protect the dehydrating cellular membrane remains enigmatic. Using giant unilamellar vesicles (GUVs) as a model membrane system, we show that encapsulated CAHS12 undergoes a reversible structural transformation that reinforces membrane integrity and preserves encapsulated components, mimicking natural anhydrobiosis. CAHS12-containing GUVs demonstrated stability for weeks and mechanical robustness under dehydration, elevated temperature, and osmotic stresses. Molecular simulations suggest that CAHS12 forms a filamentous network within the vesicle lumen that mitigates membrane collapse and preserves compartmental architecture. Synthetic cells with cell-free transcription-translation capabilities withstand desiccation and recover biochemical activities, akin to the tun state of the tardigrade. This discovery opens up synthetic cell applications in bioengineering, cold-chain-independent biomanufacturing, and adaptive biointerfaces.

synthetic biology↗

bioRxiv2025

An atlas of cell type specific regulatory effects in cattle

Understanding the genetic and molecular architecture of complex traits and artificial selection is crucial for advancing sustainable precision breeding in cattle and other livestock. Yet, how genetic variation affects cellular gene expression remains elusive in cattle. Here, by integrating 8,866 bulk RNA-seq samples and 999,192 single cells of 81 cell types in 22 bovine tissues, we presented a comprehensive atlas of regulatory variants at the cell type resolution in cattle. By colocalizing with bulk-tissue expression quantitative trait loci (beQTL), we detected 57,043 novel cell-type stratified eQTL and cell-type/state interaction eQTL in 18,153 genes, which also exhibited a stronger tissue/cell-type specificity than beQTL. By examining genome-wide associations (GWAS) of 44 complex traits, these cell-resolved eQTL were colocalized with 505 (24%) additional GWAS loci compared to beQTL. Through integrating this resource with selection signatures between dairy and beef cattle, we provided tissue/cell-specific regulatory insights into cattle breeding. Overall, the current atlas of cell-type-specific regulatory variants will serve as an invaluable resource for cattle genomics and selective breeding.

genetics↗

bioRxiv2025

Sulindac Sulfide Suppresses Oncogenic Transformation Through let-7b-Mediated Repression of K-Ras Signaling

Cell transformation is a key early event in tumorigenesis, yet the molecular mechanisms underlying its chemoprevention remain poorly defined. Here, we show that sulindac sulfide (SS), the active metabolite of the NSAID sulindac, inhibits chemically induced transformation of NIH/3T3 cells through a COX-independent mechanism. SS treatment upregulates the tumor-suppressive microRNA let-7b, which directly targets K-Ras and suppresses downstream ERK signaling. Notably, K-Ras negatively regulates let-7b via activation of ERK and LIN28B, forming a reciprocal feedback loop that drives transformation. SS disrupts this loop by downregulating p-ERK and LIN28B, thereby restoring let-7b expression. Functional analyses confirmed that let-7b, but not let-7g, is required for SS-mediated inhibition of transformation. In human colon cancer tissues and cell lines, let-7b is downregulated, but restored upon SS treatment. These findings identify a novel let-7b/K-Ras/LIN28B/ERK regulatory axis targeted by SS and provide mechanistic insight into its role in early-stage cancer chemoprevention.

cell biology↗

bioRxiv2025

Sulindac modulates the response of triple negative breast cancer to anti-PD-L1 immunotherapy

Teriple-negative breast cancer (TNBC) is a heterogeneous tumor, and there is a lack of effective therapies. Immune checkpoint inhibitors (ICIs) therapy has been widely used to treat a variety of human cancers including TNBC. Despite the FDAs approval of therapies like Atezolizumab (anti- PD-L1) and Pembrolizumab (anti-PD-1) for certain TNBC cases, more than half of all TNBC patients, especially those with low PD-L1 levels and in advanced stages, remain unresponsive. Therefore, there is urgent clinical need to find other innovative combination therapy strategy for these TNBC patients. In this study, we examined the efficacy of sulindac to enhance the response of TNBC to anti-PD-L1 immunotherapy. We utilized a 4T1 syngeneic mouse tumor model to compare the inhibitory effects of PD-L1 antibody, sulindac, and their combination on 4T1 tumor growth. We found that mice treated with combination therapy showed a significant reduction in tumor volume, along with increased infiltration of activated T lymphocytes (Granzyme B+/CD8+ T cells) in the tumor tissues. We also established a PBMC humanized mouse model to further confirmed that combination therapy could significantly reduce the tumor size of TNBC patient-derived xenografts (56S) and the combination group were found to have the most infiltrating activated human T lymphocytes (Granzyme B+/CD8+ T cells) in the tumor tissues. Immunofluorescent staining of organoids also confirmed that organoids from combination group have more CD8+ T cell and the results of organoid cell viability assay in vitro indicated that combination of sulindac with PD-L1 antibody together with activated human PBMC significantly reduce 56S organoid cell viability, which is consistent with in vivo study. When investigating the mechanism of action, first we found sulindac could downregulate exosomal PD-L1 by decreasing expression of nsMase2 which is a major regulator in production of exosomal PD-L1. Second, we demonstrated that sulindac could downregulate PD-L1 by blocking Stat3 signaling and enhancing the expression of miR-570-3p which can potentially target PD-L1, which in turn led to a further decrease in exosomal PD-L1. Previous study showed that PD-L1 antibody could be bound and consumed by exosomal PD-L1 in the blood circulation. Therefore, in combination therapy, sulindac downregulating exosomal PD-L1 leads to increased availability of PD-L1 Ab, which potentially improves the overall efficacy of anti-PD-L1 therapy. In conclusion, our findings provide unique insights into the mechanism of action and efficacy for sulindac as an immunomodulatory agent in combination with anti-PD-L1 therapy for the treatment of TNBC.

cancer biology↗

bioRxiv2025

NOTCH1 Acts as a Tumor Suppressor That Induces Early Differentiation in Head and Neck Cancer

We identified frequent inactivating notch1 mutations in HNSCC over a decade ago, indicating its role as a tumor suppressor--unlike its oncogenic function in leukemias and salivary gland tumors. However, there has been much debate in the literature regarding a possible oncogenic role in HNSCC as well, based on reports that notch1 signaling drives tumor growth and a cancer stem cell phenotype in some HNSCC tumor lines and patient samples. Clarifying whether NOTCH1 occasionally functions as an oncogenic driver in HNSCC is crucial to the prognosis and personalized therapy of patients with either wild-type or mutated NOTCH1. Here we present a systematic and comprehensive investigation unequivocally demonstrating that notch1 signaling functions as a tumor suppressor in HNSCC regardless of mutation or activation status and leads to reduction in frequency of cancer stem cells. We develop a robust gene expression signature of notch1 activation based on experimental data that when applied to patient samples shows notch1 signaling is associated with very early differentiation, an altered tumor microenvironment, and better prognosis-- consistent with a tumor suppressive role. Our work unifies the field by reconciling conflicting data and providing critical insights into the biological and clinical significance of the NOTCH1 pathway in HNSCC.

cancer biology↗