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Shen, W.

Publications and source records attributed to Shen, W..

At least 19 recordsLinked to original sources
bioRxiv2026

Cross-Tissue Inflammatory Convergence Supports a Putative Muscle-Brain Axis in Alzheimer's Disease

Background Reduced muscle strength is associated with cognitive decline and Alzheimer's disease (AD), suggesting that skeletal-muscle aging and AD-related neurodegeneration may share biological mechanisms. Vascular dysfunction, immune activation, and extracellular-matrix remodeling have been implicated in both tissues, but the extent of shared cellular and molecular programs remains unclear. We investigated cross-tissue transcriptional programs in aging skeletal muscle and AD-related brain tissue and evaluated whether related signals are detectable in peripheral blood. Methods We analyzed independent, unpaired human transcriptomic datasets from skeletal muscle (23 donors), the SEA-AD middle temporal gyrus atlas (84 donors), and peripheral blood. Donor-aware models identified age-associated changes in muscle and transcriptomic changes across continuous pseudoprogression score (CPS) in brain. Cross-tissue comparisons focused on 30 brain donors within an early CPS window. Shared tissue-derived programs were assessed in peripheral blood mononuclear cells and independently tested in frailty bulk-blood and Alzheimer's Disease Neuroimaging Initiative (ADNI) whole-blood datasets. CellOracle simulations were used to prioritize candidate transcriptional regulators. Results Aging muscle showed increased inflammatory, extracellular-matrix, and stromal communication programs. During early AD-related brain progression, vascular and immune populations showed increasing inflammatory and matrix-associated activity together with shifts in intercellular communication. Cross-tissue analysis identified six concordantly enriched pathways comprising 109 leading-edge genes in endothelial populations and four pathways comprising 51 genes in myeloid populations. Related peripheral-blood signatures varied across cohorts and cell types. However, in independent frailty and ADNI mild cognitive impairment and AD datasets, 23 of 30 predefined tissue-derived pathway-subset tests showed significant positive enrichment after false-discovery-rate correction, whereas individual gene-level bulk-blood associations did not survive correction. CellOracle analyses prioritized ETS2 and BHLHE40 as exploratory endothelial regulators whose simulated perturbation consistently reduced selected shared program scores across tissues. Conclusions Aging skeletal muscle and AD-related brain tissue exhibit convergent endothelial and myeloid inflammatory programs, with related pathway-level signals detectable in peripheral blood. These cross-tissue programs and candidate endothelial regulators provide testable hypotheses for mechanisms linking systemic aging, muscle dysfunction, and AD-related neurodegeneration.

neuroscience↗
bioRxiv2026

Representing Sex in Cardiovascular Models: Calibrating Reference Parameters from Healthy Cohorts

Reduced-order models are increasingly used to study cardiac physiology and inform patient-specific therapies. However, a model's prediction is only as reliable as its underlying parameters: representative model parameterization is essential to reflect the physiology of the populations these models are meant to represent, including biological sex. Most current models are parameterized from male or sex-agnostic data and/or focus on specific pathologies. Therefore, the goal of this work is to establish a formal parameter estimation pipeline for deriving reduced-order cardiovascular model parameter ranges that are physiologically representative of healthy women and men. We calibrated a closed-loop reduced order model of the heart and circulation separately for healthy female and male populations, using data pooled from eleven healthy cohorts. To account for parameter sensitivity and identifiability, we employed a three-stage parameter subset reduction pipeline: global sensitivity analysis (Sobol's method), collinearity screening (Fisher information matrix), and profile-likelihood identifiability analysis. Sex-specific distributions of parameters that were deemed sensitive and identifiable for each sex, ten for women and 9 for men, were obtained by Hamiltonian Monte Carlo. All the calibrated parameters showed less than 80% overlap between sexes, with the smallest overlap observed in some of the most influential parameters, such as stressed blood volume. Comparing simulations of the calibrated models against allometrically size-matched simulations showed that body size explained some, but not all, of the sex differences. The resulting parameter distributions provide reference ranges usable in future mechanistic and patient-specific simulations to contribute to more inclusive cardiovascular modeling.

bioengineering↗
bioRxiv2026

Molecular Editing in Protein Degradation: From a Dual NSD2/GSPT1 Degrader to an NSD2-Selective PROTAC and a GSPT1-Selective Molecular Glue

Both NSD2 and GSPT1 represent compelling targets for anti-cancer drug discovery. Herein, we carried out single-atom modification of LLC0424, an NSD2 degrader with GSPT1 neosubstrate engagement, to yield two structurally analogous molecules with divergent modes of action: 424-ND, an NSD2-selective degrader, and 424-GD, a GSPT1-selective degrader. 424-ND drove selective NSD2 degradation and suppressed androgen receptor (AR) signaling in prostate cancer cells. 424-GD induced selective degradation of GSPT1 and upregulated the integrated stress response markers ATF4 and ATF3. Biolayer interferometry revealed distinct ternary complex cooperativity profiles in the presence of NSD2 or GSPT1, which directly correlate with the observed biased degradation activity. Molecular dynamics and metadynamics simulations showed that the compounds adopt distinct low-energy conformational ensembles with different spatial orientations, likely underlying their divergent cooperativity and selectivity. These findings demonstrate that minimal structural alteration permits precision control over degrader target selectivity, while furnishing selective chemical probes for NSD2 and GSPT1.

cancer biology↗
bioRxiv2026

Benchmarking cell type annotation in spatial transcriptomics: resolving cellular hierarchies, biological fidelity, and dynamic cell states

Spatial transcriptomics enables the quantification of gene expression within its native tissue context, providing unprecedented insight into tissue architecture, cellular ecosystems, and local cell-cell interactions at regional and single-cell resolution. Accurate cell type annotation is a critical prerequisite for interpreting these data and is often the first and most essential step in downstream analysis. Despite rapid advances in computational methods, cell type annotation remains challenging and frequently requires extensive expert-driven manual curation based on marker-gene expression, spatial context, and prior biological knowledge. While early approaches relied primarily on transcriptional similarity, newer methods increasingly incorporate spatial information, histological features, and multimodal data to improve annotation accuracy. Nevertheless, reliable annotation remains difficult when biological interpretation requires fine-grained subtype resolution, particularly for platforms with limited gene panels, tissues undergoing dynamic cellular state transitions, and studies in which reference and query datasets differ substantially in biological context or technical modality. Here, we present a systematic benchmark of 20 state-of-the-art cell type annotation methods across four spatial transcriptomics datasets spanning diverse technologies, experimental conditions, cell numbers, and gene panel sizes. Importantly, all benchmark datasets contain expert-curated cell type labels, including wellresolved cell populations and subtype annotations, providing high-quality biological ground truth for evaluation. The benchmark encompasses both reference-based and reference-free methods representing a broad range of computational frameworks. Performance was assessed using conventional classification metrics, including accuracy and F1-based measures, together with structure-aware metrics that evaluate both cell-level annotation accuracy and preservation of higher-order biological organization. Across datasets, annotation performance varied substantially according to tissue context, reference-query similarity, and annotation granularity. Fine-grained subtype annotation and recovery of rare cell populations remained challenging for many methods, particularly in datasets capturing injury, repair, developmental, and regenerative processes characterized by continuous cellular state transitions. Notably, high classification accuracy did not necessarily correspond to preservation of global cellular relationships or biologically coherent downstream pathway and gene-set enrichment analyses. Overall, scANVI, Seurat, and TACCO consistently ranked among the top-performing methods, although their relative advantages were context dependent. Together, our results provide a comprehensive assessment of current annotation strategies for spatial transcriptomics and offer practical guidance for selecting methods that best align with specific biological questions, dataset characteristics, and analytical priorities.

bioinformatics↗
bioRxiv2026

4-Phenylbutyrate Rescue in GABRA1 Variants Associated with Developmental Epileptic Encephalopathies: from Cell and Mouse Models to Human

Disease variants in GABR genes encoding {gamma}-Aminobutyric acid type A receptor (GABAAR) subunits are major causes of developmental and epileptic encephalopathies (DEEs). There is no effective treatment for these DEEs although the GABAAR is a major target for antiseizure drugs. We previously identified the therapeutic effect of 4-phenyl-butyrate (PBA) in Gabrg2+/Q390X knockin DEE mice and now test the effect of the drug in GABRA1 variants that encode the 1 subunit. We used a multidisciplinary approach including in silico structural modeling, flow cytometry, patch clamp recordings and bio-chemistry in conjunction with differential tagging of the wild-type and the mutant alleles to evaluate the effect of PBA on rescue of GABAAR subunit expression, surface trafficking, and function in vitro in heterologous HEK293T cell model and in vivo in Gabra1+/A322D mice. We found that both total and cell surface 1 expression was reduced when the variant 1 protein was present; suggesting reduced functional receptor on the cell membrane and synapse. Patch clamp recordings identified 1 variants reduced GABA-evoked current amplitude. In silico prediction indicated reduced protein stability for GABRA1 variants indicated by negative {Delta}{Delta}G values. PBA increased both total and surface expression of wildtype 1 and 1 variants; and improved expression of both wildtype and variant 1 alleles when these were co-expressed. Importantly, PBA also increased the GABAAR expression in the thalamus of the Gabra1+/A322D mice. This study indicates that PBA is a promising treatment option for DEEs associated with GABRA1 mutations. Our previous work has demonstrated that PBA improves proteostasis by enhancing expression of the wildtype allele, repairing the mutant allele, and reducing endoplasmic reticulum stress. Therefore, it can mitigate seizures and improve neurobehavioral phenotypes at behavioral levels. Based on this and our previous work on GABRG2 and SLC6A1 mutations, we propose that PBA holds promise as a common medicine for multiple genetic neurologic disorders that share the proteostasis pathology with a broad clinical application in DEEs.

neuroscience↗
bioRxiv2026

Cell membrane proteome profiling uncovers molecular signatures and GPCR regulators underlying diet-induced obesity and exercise-mediated adaptation

Cell membrane proteins (CMPs), notably G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), represent the largest class of druggable targets. Despite their therapeutic importance, how the CMP landscape is systemically remodeled during metabolic disease progression and in response to exercise remains poorly understood. Here, we constructed the most comprehensive CMP proteome atlas to date across 22 male mouse tissues and established the first multi-tissue map of GPCR-associated protein hormones/prohormones. Integrated CMP proteomic and transcriptomic analysis revealed that diet-induced obesity and its progression to type 2 diabetes remodel the CMP repertoire in patterns distinct from those induced by exercise. We found that numerous GPCRs and RTKs critical for energy homeostasis are dysregulated during obesity in a tissue-specific manner, and these alterations are reversed to varying extents by exercise training. Importantly, our CMP-centric omics study identified two parathyroid hormone receptors (PTHRs) in the hypothalamus as negative regulators of feeding and body weight. Genetically silencing these hypothalamic PTHRs led to severe obesity even on a chow diet and markedly blunted exercise-induced weight loss. Collectively, our study provides not only new insights into systematic CMP regulation underlying metabolic deterioration versus exercise adaptation, but also nominates potential receptor targets for obesity management.

biochemistry↗
bioRxiv2026

A cerebellar cognitive rheostat bidirectionally controls attention

Attention requires filtering distractors and amplifying signals, processes classically attributed to cortico-thalamic networks. Here, we reveal that the cerebellum operates as a bidirectional "cognitive rheostat" to optimize attentional states. In mice, the anterior and posterior cerebellar vermis exert opposing control over attention. Granule cells in the anterior vermis are functionally suppressed to gate sensorimotor noise via reticular nucleus-driven feedforward inhibition. Conversely, posterior granule cells are recruited by pontine inputs to amplify cognitive signals, a process relying on Grin1-mediated NMDA receptor plasticity. Circuit-specific manipulations targeting this push-pull mechanism, or localized pharmacological modulation, successfully rescued attentional deficits in an ADHD mouse model. These findings fundamentally expand the cerebellums role beyond motor coordination, identifying a topographic circuit algorithm essential for cognitive control.

animal behavior and cognition↗
bioRxiv2026

TREM2 agonist antibody rebuilds the resident synovial macrophage lining barrier in rheumatoid arthritis

Rheumatoid arthritis (RA) can be viewed as a disease of barrier failure, in which CX3CR1+/TREM2+ synovial tissue-resident macrophages that form the lining barrier over cartilage and bone become fragmented and disorganized. However, how to therapeutically rebuild this barrier--and how macrophage states transition during repair--remain unclear. We engineered TR-Ab19, a mouse-selective agonistic antibody against TREM2, as a precision tool to initiate and interrogate barrier repair in vivo. TR-Ab19 engages TREM2-linked downstream signaling and redirects synovial macrophages from Clec4d+ inflammatory/proliferative programs toward TREM2+CX3CR1+Aqp1+ barrier-like states, thereby rebuilding the lining barrier. Across collagen-induced arthritis (CIA) and serum-transfer arthritis (STA) models, TR-Ab19 reduces synovitis, preserves cartilage and bone microarchitecture, limits osteoclastogenesis, and attenuates systemic cytokines and B-cell abnormalities. Single-cell RNA-seq with trajectory and cell-cell communication analyses reveal a TREM2-dependent shift toward a barrier-dominant macrophage ecosystem. Together, these findings establish antibody-mediated reprogramming of resident synovial macrophages as a barrier-centered strategy for RA and provide a framework for instructing macrophage niches in chronic inflammation.

bioengineering↗
bioRxiv2026

Accumulation of Extracellular GABA, Impaired GABAergic Neurotransmission and 4-Phenylbutyrate Rescue in Mice of SLC6A1 Variant-Mediated Disorders

Mutations in SLC6A1 encoding GABA transporter 1 are a leading monogenic cause of developmental and epileptic encephalopathies, severe neurodevelopmental disorders lacking effective treatments. We previously demonstrated that 4-phenylbutyrate restored molecular and functional deficits, and reduced seizures in a Slc6a1 loss-of-function mouse, motivating a promising ongoing clinical trial. Here, we show this mouse exhibits accumulation of extracellular GABA, impaired neurotransmission, and reduced GABA uptake; and demonstrate that 4-phenylbutyrate rescues these abnormalities.

neuroscience↗
bioRxiv2026

Medea: An omics AI agent for therapeutic discovery

Therapeutic hypotheses can transfer across diseases but their relevance depends on biological context. The same target, perturbation, or treatment can produce different effects across cell types, disease states, genetic backgrounds, and patients. Therapeutic reasoning therefore requires methods that preserve context, test when evidence supports transfer, and identify where context-specific effects limit it. Although AI agents can perform therapeutic analyses, existing systems often fail to preserve biological context over long workflows, verify intermediate computational steps, or reconcile conflicting evidence across datasets and literature. Here, we present Medea, an AI agent for therapeutic reasoning across biological contexts. Medea executes multi-step analyses using biological tools, machine learning models, and literature retrieval while enforcing verification during planning, execution, and evidence synthesis. We evaluate Medea across 5,673 open-ended analyses in three domains: cell type specific therapeutic target nomination in five diseases and 29 cell types, synthetic lethality prediction in 7 cancer cell lines, and immunotherapy response prediction from multimodal patient profiles. Using a previously unpublished epistatic miniarray profiling screen performed under two DNA-damaging treatments, we evaluate Medea on predicting synthetic lethality among 238,046 gene-gene pairs in yeast. Medea predicts these experimentally measured synthetic lethal interactions, indicating that its performance reflects biological relevance rather than information leakage from benchmark datasets. Across these evaluations, Medea improves performance over large language models, reasoning models, biomedical agents, and specialized machine learning models while maintaining low failure rates and calibrated abstention. These results show that verifiable AI agents can perform therapeutic analyses across biological contexts.

bioinformatics↗
bioRxiv2025

β-Nicotinamide mononucleotide: a novel broad-spectrum CRISPR inhibitor

CRISPR-Cas systems have revolutionized genome editing with their precision and versatility, enabling transformative applications in various fields, especially in the treatment of genetic diseases. However, the clinical translation of this technology is hindered by challenges such as off-target effects and uncontrolled nuclease activity. At the same time, it has the possibility of causing biosecurity risks, underscoring the urgent need for reliable regulatory tools. Existing CRISPR inhibitors, primarily anti-CRISPR protein or exogenously synthesized small molecules, are limited by their specificity or bioavailability and long research period, unable to address the diverse CRISPR nucleases used in research and therapy. Based on the phenomena obtained from various in vitro and cell experiments, combining molecular dynamics simulation and bio - layer interferometry (BLI) analysis, here we report a naturally occurring small-molecule {beta}-nicotinamide mononucleotide (NMN), the first known endogenous metabolite with broad-spectrum inhibitory activity against multiple CRISPR-associated proteins (Cas9, Cas12, and Cas13) through various mechanisms. Our findings establish NMN as a dual-purpose tool, which reduces cell damage caused by gene editing and mitigates risks of unintended genetic modifications in research and clinical settings. This discovery further shortens the distance between basic medicine and translational medicine, providing a new approach for developing endogenous regulatory molecules in genome engineering.

genetics↗
bioRxiv2025

Ampk alpha2 T172 Activation Dictates Exercise Performance and Energy Transduction in Skeletal Muscle

AMPK (5'-AMP-activated protein kinase) is an energetic sensor for metabolic regulation and integration. Here, we employed CRISPR/Cas9 to generate non-activatable Ampk knock-in (KI) mice with mutation of threonine 172 phosphorylation site to alanine, circumventing the limitations of previous genetic interventions that disrupt the protein stoichiometry. KI mice of Ampk2, but not Ampk1, demonstrated phenotypic changes with increased fat-to-lean mass, impaired endurance exercise capacity, and diminished mitochondrial maximal respiration and conductance in skeletal muscle. Integrated temporal multi-omic analysis (proteomics/phosphoproteomics/metabolomics) in skeletal muscle at rest and during exercise establishes a pleiotropic yet imperative role of Ampk2 T172 activation for glycolytic and oxidative metabolism, mitochondrial respiration, and contractile function. Importantly, there is a significant overlap of skeletal muscle proteomic changes in Ampk2 T172A KI mice with that of type 2 diabetic patients. Our findings suggest that Ampk2 T172 activation is critical for exercise performance and energy transduction in skeletal muscle and may serve as a therapeutic target for type 2 diabetes.

molecular biology↗
bioRxiv2025

Chromosome-Specific Aneuploidy Engineering via dCas9-Induced Centromeric Chromatin Relaxation

Aneuploidy, the gain or loss of chromosomes, is prevalent in both normal and disease conditions, however, experimental approaches to engineer and study aneuploidy remain limited, leaving its functional significance under-characterized. Here, we present CRISPR-Taiji (CRISPRt), an efficient method for inducing chromosome-specific mis-segregation and aneuploidy generation across all 24 human chromosomes via dead Cas9 (dCas9)-induced centromeric chromatin relaxation. Using CRISPRt with scRNA-seq, we generated the first comprehensive transcriptomic alteration landscape of nearly all autosomal aneuploidies at chromosome-arm resolution. This genotype-phenotype map provides causal evidence linking recurrent aneuploidies in clear cell renal cell carcinoma (ccRCC) to molecular and clinical phenotypes observed in patient tumors. Notably, chromosome 3(p) loss, the ccRCC initiating event, specifically drives strong interferon signaling activation, offering novel insights into ccRCC tumorigenesis and immune modulation. Overall, we establish CRISPRt as a simple, efficient and scalable approach for chromosome-specific aneuploidy engineering and characterization in preclinical models to advance aneuploidy research across diverse biological contexts.

genomics↗
bioRxiv2025

Natural self-attenuation of pathogenic viruses by deleting the silencing suppressor coding sequence for long-term plant-virus coexistence

Potyviridae is the largest family of plant-infecting RNA viruses. All members of the family (potyvirids) have positive-sense single-stranded RNA genomes, with polyprotein processing as the main expression strategy. The 5-proximal regions of their genomes encode two types of leader proteases: the serine protease P1 and the cysteine protease HCPro. However, their arrangement and sequence composition vary greatly among genera or even species. The leader proteases play multiple important roles in different potyvirid-host combinations, including RNA silencing suppression and virus transmission. Here, we report that viruses in the genus Arepavirus, which encode two HCPro leader proteases in tandem (HCPro1-HCPro2), can naturally lose the coding sequences for these two proteins during infection. Notably, this loss is associated with a shift in foliage symptoms from severe necrosis to mild chlorosis or even asymptomatic infections. Further analysis revealed that the deleted region is flanked by two short repeated sequences in the parental isolates, suggesting that recombination during virus replication likely drives this genomic deletion. Reverse genetic approaches confirmed that the loss of leader proteases weakens RNA silencing suppression and other critical functions. A field survey of areca palm trees displaying varied symptom severity identified a transitional stage in which full-length viruses and deletion mutants coexist in the same tree. Based on these findings, we propose a scenario in which full-length isolates drive robust infections and facilitate plant-to-plant transmission, eventually giving rise to leader protease-less variants that mitigate excessive damage to host trees, allowing long-term coexistence with the perennial host. To our knowledge, this is the first report of potyvirid self-attenuation via coding sequence loss. Author summaryPlant viruses typically persist throughout the lifespan of their host plants, employing multiple strategies to ensure long-term survival. This study reveals an unusual self-attenuation mechanism in which potyvirids, likely through recombination, discard a large genomic fragment containing the RNA silencing suppressor coding sequence. This deletion reduces viral pathogenicity, enabling a peaceful long-term virus-plant coexistence. Meanwhile, the attenuated viruses may function as natural vaccines, protecting plants from reinfection by the full-length pathogenic strains or related variants. These findings highlight a direct link between viral evolution and long-term coexistence, suggesting that such adaptations may promote mutual benefits. Understanding these dynamics could provide valuable insights into virus-host interactions and inspire new approaches to plant disease management.

pathology↗
bioRxiv2024

Heat Acclimation in Mice Requires Preoptic BDNF Neurons and Postsynaptic Potentiation

Heat acclimation (HA) is a key adaptive response in mammals to repeated heat exposure, essential for fitness and survival1-3. HA improves cardiovascular function, thermal comfort, and exercise capacity4, 5. However, the lack of a genetically tractable model has hindered understanding of the molecular and neural mechanisms underlying HA. Here, we show that 10 days of daily 38{degrees}C exposure lowers core body temperature (Tcore) and reduces anxiety during subsequent heat exposures in mice. HA increases brain-derived neurotrophic factor (BDNF) expression in the medial preoptic area (MPO). BDNF-expressing MPO neurons (MPOBDNF) show increased intrinsic heat sensitivity after HA. These neurons orchestrate downstream targets in the dorsomedial hypothalamus (DMH) and rostral raphe pallidus (rRPa) to mediate HA effects. BDNF, acting through its receptor tropomyosin-related kinase B (TrkB) in the DMH, facilitates the anxiolytic effect of HA by enhancing excitatory synaptic connections between MPOBDNF and DMH neurons. This study provides new insights into HA mechanisms, setting the stage for future research on heat stress reduction and exercise optimization.

neuroscience↗
bioRxiv2024

High-resolution imaging atlas reveals context-dependent role of pancreatic sympathetic innervation in diabetic mice

Gaining a better understanding of how sympathetic nerves impact pancreatic function is helpful for understanding diabetes. However, there is still uncertainty and controversy surrounding the roles of sympathetic nerves within the pancreas. To address this, we utilize high-resolution imaging and advanced three-dimensional (3D) reconstruction techniques to study the patterns of sympathetic innervation and morphology in islets of adult WT and diabetic mice. Our data shows that more than [~]30% /{beta}-cells are innervated by sympathetic nerves in both WT and diabetic mice. Also, sympathetic innervated /{beta}-cells are reduced in DIO mice, whereas sympathetic innervated {beta}-cells are increased in db/db mice. Besides, in situ chemical pancreatic sympathetic denervation (cPSD) improves glucose tolerance in WT and db/db mice, but decreases in DIO mice. In situ cPSD also enhances insulin sensitivity in diabetic mice without affecting WT mice. Overall, our findings advance our comprehension of diabetes by highlighting the distinctive impact of pancreatic sympathetic innervation on glucose regulation. HighlightsPancreatic sympathetic innervation plays an important role in glucose homeostasis. In our study, we systematically investigate sympathetic innervation in the islets of WT and diabetic mice. O_LI45.9% -cells and 31.8% {beta}-cells are innervated by sympathetic nerves in 10-week-old WT mice. C_LIO_LISympathetic innervated /{beta}-cells are reduced in DIO mice, whereas sympathetic innervated {beta}-cells are increased in db/db mice. C_LIO_LIUnlike the core-mantle structure observed in WT and DIO mice, -cells and {beta}-cells are intermixed in db/db mice. C_LIO_LIPancreatic sympathetic denervation elicits varied responses across diabetic models, where it improves glucose tolerance and insulin sensitivity in db/db mice, yet it increases insulin sensitivity but reduces glucose tolerance in DIO mice. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/623708v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@183be78org.highwire.dtl.DTLVardef@4dc76borg.highwire.dtl.DTLVardef@5f5ca0org.highwire.dtl.DTLVardef@ba3cc7_HPS_FORMAT_FIGEXP M_FIG Summary of morphological and physiological phenotypes in diabetic mice. All data are normalized to that of WT-10 mice. The numbers of "+" refer to their relative numbers. {uparrow} or {downarrow} refers to increase or decrease, ns refers to "not significant". "-" refers to the experiment has not been carried out. C_FIG

neuroscience↗
bioRxiv2024

KLF7-Regulated ITGA2 as a Therapeutic Target for Inhibiting Oral Cancer Stem Cells

Cancer stem cells (CSCs) play crucial roles in tumor metastasis, therapy resistance, and immune evasion. Identifying and understanding the factors that regulate the stemness of tumor cells presents promising opportunities for developing effective therapeutic strategies. In this study on oral squamous cell carcinoma (OSCC), we confirmed the key role of KLF7 in maintaining the stemness of OSCC. Using chromatin immunoprecipitation sequencing and dual-luciferase assays, we identified ITGA2, a membrane receptor, as a key downstream gene regulated by KLF7 in the maintenance of stemness. Tumor sphere formation assays, flow cytometry analyses, and in vivo limiting dilution tumorigenicity evaluations demonstrated that knocking down ITGA2 significantly impaired stemness. When bound to its ECM ligand, type I collagen, ITGA2 activates several stemness-related pathways, including PI3K-AKT, MAPK, and Hippo. TC-I 15, which inhibits the ITGA2-collagen interaction, showed a synergistic anti-tumor effect when combined with cisplatin in both in vitro and xenograft models. In summary, we reveal that the KLF7/ITGA2 axis is a crucial modulator of stemness in OSCC. Our findings suggest that ITGA2 is a promising therapeutic target, offering a novel anti-CSC strategy. Highlights1) KLF7 as a key molecule in maintaining oral cancer stemness. 2) ITGA2as a key downstream gene regulated by KLF7 in the maintenance of stemness. 3) ITGA2 interacts with extracellular matrix type I collagen, activating stemness-related pathways and promoting YAP1 nuclear translocation to sustain OCSCs. 4) ITGA2 as a novel anti-CSC target, providing a new strategy to overcome OSCC drug resistance.

cancer biology↗