Biology subjects

Zheng, B.

Publications and source records attributed to Zheng, B..

At least 19 recordsLinked to original sources

bioRxiv2026

Feed-based delivery of plasmid DNA using milk-derived extracellular vesicle-polyethylenimine complexes enables hepatic transgene expression in goldfish

Oral administration through feed offers a non-invasive, cost-effective, and scalable approach for gene delivery in aquaculture. However, gastrointestinal degradation and intestinal barriers severely limit the oral delivery of plasmid DNA (pDNA). In this study, we developed a ternary nanocarrier composed of bovine milk-derived extracellular vesicles (MEVs), polyethylenimine (PEI), and pDNA (MPPs) to investigate its potential for functional gene delivery to the goldfish (Carassius auratus) liver (hepatopancreas). The resulting MPPs exhibited a relatively uniform particle size, high pDNA loading efficiency, and protection against nuclease-mediated degradation. Formulation optimization in HEK293T cells identified an MEV:PEI:pDNA mass ratio of 16.7:4.1:1, which supported robust EGFP reporter expression. Following oral administration of DiD-labeled MEVs through feed, fluorescence signals were detected in the goldfish hepatopancreas within 2 h and remained detectable at 6 h. After a single feeding of MPP-containing feed, hepatic luciferase mRNA expression peaked at 24 h and gradually declined to near-baseline levels by 72 h. During 14 consecutive days of feeding, luciferase protein expression was detectable from day 3, with progressively increased protein abundance and enzymatic activity observed on days 7 and 14. Collectively, these findings demonstrate the feasibility of feed-based MPP administration for inducing functional transgene expression in the goldfish hepatopancreas, providing a promising foundation for developing non-invasive nucleic acid delivery strategies in aquaculture.

molecular biology↗

bioRxiv2026

A microbiota-driven neuroepithelial feed-forward circuit drives gastroesophageal junction tumorigenesis

The gastroesophageal junction (GEJ) is continuously exposed to refluxed bile acids and microbial perturbations, yet how these environmental cues are converted into persistent oncogenic signaling is unknown. Here we show that bile acid remodeling enriches the oral commensal Prevotella melaninogenica at the GEJ, where bacterial succinate activates both vagal sensory neurons and SUCNR1-expressing tuft cells. Activated tuft cells release 15-deoxy-12,14-prostaglandin J2 (15-d-PGJ2), which sensitizes sensory neurons and sustains nerve remodeling, while neuronal CGRP drives expansion and tuft-cell differentiation of neuro-responsive epithelial progenitors through RAMP1. This self-reinforcing microbiota-neuron-epithelium circuit promotes dysplastic progression, and its genetic or pharmacological disruption, including with the approved CGRP antagonist rimegepant, suppresses tumor development, revealing an interceptable mechanism linking environmental dysbiosis to cancer initiation through neural circuits.

cancer biology↗

bioRxiv2026

Neogenin-1 marks myeloid-primed fetal hematopoietic stem cells that undergo progressive lineage-restriction with age

During aging, hematopoietic stem cells (HSCs) increasingly shift from balanced to myeloid-biased differentiation, resulting in reduced lymphoid output and impaired adaptive immunity. The question of whether this lineage bias is established in a subset of HSCs during early development or primarily emerges with aging warrants further investigation. Here, we investigate whether myeloid-biased HSCs (my-HSCs) are established at the fetal liver stage by specifically examining Neogenin-1 (NEO1), a previously defined marker of my-HSCs. We identify two distinct populations of Hoxb5+ HSCs in the fetal liver: NEO1+ and NEO1-, with NEO1+ HSCs exhibiting transcriptional and functional characteristics consistent with my-HSCs. With age, my-HSC-associated transcriptional programs become increasingly reinforced across the Hoxb5+ pHSC compartment, with NEO1+ cells showing early enrichment of this program and both NEO1+ and NEO1- cells acquiring broader myeloid-biased features in aging. These findings suggest that lineage programming can begin early in development and is further shaped by age-related changes, potentially contributing to the functional decline observed in the aging hematopoietic system.

developmental biology↗

bioRxiv2026

Pre-existing antibiotic tolerance facilitates plasmid-mediated carbapenem resistance evolution in clinical Klebsiella pneumoniae

Antibiotic tolerance enables bacteria to survive bactericidal antibiotic exposure and has been linked to resistance evolution in laboratory systems and individual infections, but its role in plasmid-mediated resistance evolution in clinical populations remains unclear. Here, we analyzed a longitudinal collection of more than 800 clinical Klebsiella pneumoniae isolates spanning 1997-2020. Among 779 minimum inhibitory concentration (MIC)-defined ertapenem-susceptible isolates, 137 (17.6%) displayed hidden ertapenem tolerance, defined by enhanced survival after 6 h at 30 times the isolate-specific ertapenem MIC, mostly without extended lag time or reduced growth rate. Tolerance was detected before local ertapenem introduction and was enriched among ertapenem-resistant isolates, supporting a population-level association between pre-existing tolerance and the emergence of carbapenem resistance. Genomic and plasmid-curing analyses separated plasmid-mediated carbapenem resistance from plasmid-independent antibiotic tolerance. Moreover, tolerant recipient backgrounds enhanced resistance plasmid acquisition, preserved viable recipients following antibiotic exposure and accelerated ceftazidime-avibactam resistance evolution. A phylogeny-guided variant-enrichment analysis further identified the uhpABC regulatory operon as a candidate tolerance-associated locus, and coordinated expression of the complete operon increased ertapenem survival. Together, these findings identify clinical antibiotic tolerance as a pre-existing, MIC-hidden phenotype that can facilitate plasmid-mediated carbapenem resistance evolution in K. pneumoniae.

microbiology↗

bioRxiv2026

Outer membrane stiffness gates multidrug tolerance

Bactericidal antibiotics initiate killing through class-specific target damage, yet the cellular properties that determine whether antibiotic-induced damage remains reversible or progresses to irreversible death remains unclear. Here, using kanamycin-centered evolution in Escherichia coli, we identified a multidrug-tolerant mutant that exhibits increased survival across aminoglycosides, {beta}-lactams, quinolones and polymyxins without altered minimum inhibitory concentrations. We demonstrate that mechanistically distinct antibiotics converge on outer membrane destabilization, revealing a shared downstream vulnerability during killing. Elevated outer membrane stiffness limits antibiotic-induced envelope destabilization, thereby gating multidrug tolerance. Orthogonal chemical and physical perturbations further established a quantitative relationship between outer membrane stiffness and antibiotic survival across drug classes. Our findings reveal outer membrane stiffness as a previously unrecognized physical basis of multidrug tolerance and suggest that modulating bacterial envelope mechanics may provide new opportunities for antimicrobial intervention.

microbiology↗

bioRxiv2026

Transferable IncX3-blaNDM-15 in an uncommon ST580 Klebsiella pneumoniae recovered during paediatric intensive-care surveillance

Objective: Carbapenem-resistant Klebsiella pneumoniae harboring blaNDM poses a serious threat to public health; however, blaNDM-15 remains poorly characterized outside the dominant epidemic lineages. Methods: We characterized K. pneumoniae strain ETFK6090, isolated from a perianal surveillance swab of an 11-month-old immunocompromised child in a paediatric intensive care unit. Investigations included antimicrobial susceptibility testing, broth conjugation, S1 nuclease PFGE with Southern blotting, complete genome sequencing, and comparative genomic analysis against 465 curated blaNDM-positive K. pneumoniae genomes from 37 countries. Results: ETFK6090 belonged to ST580 and exhibited resistance to carbapenems, ceftazidime-avibactam, broad-spectrum cephalosporins, fluoroquinolones, gentamicin, chloramphenicol and trimethoprim-sulfamethoxazole; amikacin and fosfomycin retained low MICs. The complete genome comprised one chromosome and five plasmids, blaNDM-15 was localized on a 46,161-bp IncX3 plasmid, confirmed by Southern blotting. Conjugation into Escherichia coli EC600 transferred carbapenem and cephalosporin resistance, confirming in vitro mobility. The blaNDM-15 genetic environment retained a conserved blaNDM module, with IS-mediated rearrangements at the downstream boundary. In the global comparison, blaNDM-1 and blaNDM-5 predominated, the ST580-blaNDM-15 combination was exceedingly rare, and ETFK6090 constituted a distinct branch apart from major epidemic lineages. Conclusions: A transferable IncX3-blaNDM-15 plasmid can emerge in an uncommon ST580 background, underscoring the necessity to extend genomic surveillance of carbapenem-resistant K. pneumoniae beyond dominant epidemic clones, particularly in high-risk paediatric and intensive-care settings.

microbiology↗

bioRxiv2026

Sensory neurons encode long-term inflammatory memory that promotes gastric regeneration and tumorigenesis

Inflammatory memory has emerged as a fundamental principle by which prior injury shapes future tissue responses, yet whether sensory neurons participate in long-term tissue memory remains unknown. Here, we show that vagal sensory neurons acquire a durable, experience-dependent state following gastric injury or Helicobacter pylori infection, leading to enhanced regeneration, metaplasia, and tumor progression upon re-injury. This neuronal program is stable, functionally transferable, and sufficient to drive epithelial responses in vivo. Mechanistically, injury-activated ILC2s establish sensory neuronal memory through IL-13-dependent epigenetic remodeling, inducing SMYD4-mediated H3K4 trimethylation and promoting CGRP-dependent activation of gastric epithelial cells. Together, our findings support a model in which tissue memory is not restricted to epithelial or immune compartments but emerges through coordinated long-term adaptations across multiple cellular systems. Within this framework, sensory neurons provide a persistent substrate for recall responses, linking prior inflammatory experience to sustained epithelial plasticity and cancer susceptibility. HIGHLIGHTSO_LISensory neurons function as a durable compartment of tissue memory. C_LIO_LICGRP-RAMP1 signaling couples neuronal memory to gastric stem cells. C_LIO_LIILC2-derived IL-13 establishes sensory neuronal memory programs. C_LIO_LISMYD4-mediated H3K4me3 stabilizes long-term neuronal memory. C_LIO_LINeuronal memory promotes gastric regeneration and tumor susceptibility. C_LI

cancer biology↗

bioRxiv2026

BAYESIAN STATE-SPACE MODEL FOR JOINT INFERENCE OF OSCILLATORY DYNAMICS AND POINT-PROCESS COUPLING

Under a range of behavioral and physiological conditions, spike times and local field potential (LFP) oscillations exhibit phase coupling within specific frequency bands. Classical measures such as spike-field coherence (SFC) and the phase-locking value (PLV) quantify this coupling but estimate the LFP spectrum independently of spike timing. We introduce Joint SSMT, a Bayesian state-space framework that jointly infers LFP spectrograms and spike-field coupling strength. The model treats narrowband LFP activity as a latent process evolving in continuous time, with spike trains linked to the complex spectral state through a Bernoulli-logistic model. In simulations, Joint SSMT accurately recovers coupling strength, denoises the spectrogram, and uses spike timing to resolve fine temporal structure in the LFP. Applied to propofol anesthesia data, the model identifies coupling at a specific slow-oscillation frequency where SFC and PLV report only broad low-frequency coupling. We extend Joint SSMT to trial-structured experiments and apply it to primate recordings during an associative learning task, revealing frequency-specific coupling in hippocampus and prefrontal cortex. We also derive closed-form expressions for SFC and PLV as functions of the generative model parameters. Across simulations and two primate datasets, Joint SSMT provides more frequency-specific coupling estimates with principled uncertainty quantification than classical PLV and SFC.

neuroscience↗

bioRxiv2026

Pre-clinical efficacy of a C4BP hexameric IgG Fc fusion protein against Neisseria gonorrhoeae

Gonorrhea is the second most common bacterial sexually transmitted infection and affects about 80 million people worldwide annually. The causative agent, Neisseria gonorrhoeae, has become resistant to almost every antibiotic used for its treatment. There is no licensed vaccine against gonorrhea. Therefore, there is an urgent need to develop novel prevention and treatment strategies to curb the spread of gonorrhea. The gonococcus has evolved several mechanisms to evade complement, a key arm of immune defenses against this pathogen, including binding of the human complement inhibitors Factor H (FH) and C4b-binding protein (C4BP). We previously showed that chimeric molecules fusing the gonococcal binding domains of FH and C4BP to IgG Fc and IgM Fc, respectively, mediate complement-dependent killing of gonococci in vitro and attenuate gonococcal colonization of mouse vaginas when administered topically. Here, we fused C4BP domains 1 and 2, which contain the gonococcal binding region, to IgG Fc bearing the IgM tail-piece to facilitate Fc hexamerization. This molecule, called C4BP-Hexa IgG Fc, showed [~]650-fold greater complement-dependent bactericidal activity on a molar basis than monomeric C4BP-IgG1 Fc. C4BP-Hexa IgG Fc enhanced association with and uptake by human neutrophils in a complement-independent manner. Despite off-target complement activation in solution, C4BP-Hexa IgG Fc reduced both the duration and the bacterial burden of gonococcal vaginal colonization in human FH and C4BP transgenic mice when administered intravaginally daily. In conclusion, we show proof-of-concept of the efficacy of a hexameric C4BP IgG Fc fusion molecule against N. gonorrhoeae, which could aid in the fight against this multidrug-resistant pathogen.

immunology↗

bioRxiv2025

Transforming a Fragile Protein Helix into an Ultrastable Scaffold via a Hierarchical AI and Chemistry Framework

The rational design of proteins that maintain structural integrity under concurrent thermal, mechanical, and chemical stress remains a challenge in molecular engineering. We present a hierarchical framework that transforms an -helical domain into an ultrastable scaffold by integrating AI-guided design with foundational chemical principles. This approach progresses from global architectural reinforcement, using multiple AI tools to create a stabilized four-helix bundle, to local chemical tuning, where AlphaFold3 guides the installation of salt bridges and metal-coordination motifs. A computational pipeline using physics-based screening such as molecular dynamics (MD) simulations efficiently distilled millions of designs into a minimal candidate set. The resulting -helical proteins exhibit unprecedented multi-axis stability, with mechanical unfolding forces exceeding 200 pN, thermal resilience >100 {degrees}C, and high resistance to chemical denaturants. By systematically dissecting the contributions of hydrophobic packing, electrostatics, and metal coordination, we establish a general blueprint for imparting extreme robustness. This work bridges AI-driven structural generation with chemical precision, advancing the creation of durable proteins for mechanistic studies and synthetic biology.

biophysics↗

bioRxiv2025

BRD2 bridges TFIID and histone acetylation to promote transcriptional initiation

Members of the bromodomain and extraterminal domain (BET) protein family play a central role in transcription by RNA Polymerase II (Pol II). Small-molecule inhibitors that block interaction between BET bromodomains and acetylated histones have been developed to achieve therapeutic benefit. However, the BET protein BRD4 does not require bromodomains to perform its major transcriptional elongation function, and the mechanisms by which other BET proteins regulate transcription remain incompletely understood. Addressing the disparity between pan-BET degraders and BRD4-specific depletion, we report that the BET protein BRD2 generally functions to promote transcriptional initiation in a bromodomain-dependent manner at both promoters and enhancers in human cells. We demonstrate that BRD2 bromodomains preferentially bind to tetra-acetylated histones harboring MOF-mediated H4K16ac, while the BRD2 C terminal domain facilitates recruitment of TFIID. Our studies provide mechanistic insight into the distinct roles of BRD2 in transcriptional initiation through the recruitment of TFIID and BRD4 in transcriptional elongation through the recruitment of CDK9 and controlling proper regulation of gene expression.

biochemistry↗

bioRxiv2025

Integrating molecular and physiological approaches to quantify genetic controls for wheat development and improve phenotyping

Disentangling genotype x environment (GxE) effects is critical to understand the performance of wheat across different environments. A framework for doing this was previously presented in a model that integrated knowledge of crop physiology and the Vrn gene feedback loop to explain and predict the time of anthesis. The aims of this study were: 1) provide an updated description of the Cereal Anthesis Molecular Phenology (CAMP) model; 2) to verify the models assumptions regarding the relationship between Vrn gene expression and the timing of phenological stages in a set of diverse genotypes and environments; 3) to use the CAMP model to establish a phenotyping strategy for use in genetic studies and model parameterisation. Six wheat genotypes with a range of cool temperature and photoperiod sensitivities were evaluated. Apical development, final leaf number (FLN) and temporal expression of Vrn1, Vrn2 and Vrn3 were compared with model predictions. There was a clear relationship between FLN responses to cool temperature and photoperiod, the timing of phenological events and the patterns of Vrn gene expression for all genotypes. There was general agreement between the temporal patterns of foliar gene expression observed with those assumed by CAMP, but some obvious discrepancies. These may be related to differences between gene expression in foliar (observed) and apical (assumed by the model) parts of the plant, or differences in the way observed and modelled gene expression are scaled. Overall, the model described all the observed development responses to environment and provides a basis for building quantitative predictions of field-based development from genotypic and environmental data. A protocol is presented for phenotyping wheat using FLN measured in specific combinations of temperature and photoperiod. It allows easy and unconfounded measure of key developmental phenotypes that clearly relate to the genetic make-up of the plants and underlying gene expression profiles.

plant biology↗

bioRxiv2025

Sodium Selenite Alleviates Hyperglycemia-aggravated Cerebral Ischemic Injury by Mediating Apoptosis through the Fas/FasL Signaling Pathway

ObjectiveTo investigate the intervention mechanism of sodium selenite in alleviating hyperglycemia-induced cerebral ischemia/reperfusion (I/R) injury through the Fas/FasL/NF-{kappa}B/PUMA pathway. MethodsThe SD rat model of hyperglycemia-induced cerebral I/R injury and the HT22 cell model of high-glucose oxygen deprivation/reoxygenation (OD/R) were constructed to systematically evaluate the neuroprotective effect of sodium selenite and its regulatory effect on the Fas/FasL/NF-{kappa}B/PUMA pathway. ResultsThe infarct volume, neurological dysfunction, metabolic level, and apoptosis level in the HG group were significantly higher than those in the NG group. Sodium selenite improved the infarct volume, neurological dysfunction, metabolic level, and apoptosis level in the HG group, and regulated the Fas/FasL/PUMA apoptotic pathway to alleviate injury. In vitro experiments showed that sodium selenite significantly improved morphological damage caused by high-glucose OD/R, increased cell viability, and reduced the expression of apoptotic factors. The application of Fas and FasL inhibitors and knockdown of PUMA expression indicated that sodium selenite alleviated cell apoptosis by inhibiting the activation of the Fas/FasL/PUMA pathway. ConclusionSodium selenite alleviates hyperglycemia-exacerbated cerebral I/R injury by regulating the Fas/FasL/NF-{kappa}B/PUMA signaling pathway.

pathology↗

bioRxiv2025

Netrin-1 promotes pancreatic tumorigenesis and innervation through NEO1.

Nerves have been shown to regulate cancer progression. However, a clear demonstration of a role for axon guidance molecules in pancreatic tumorigenesis, innervation, and metastasis has been lacking. Using murine KrasG12D-mutant pancreatic organoids, we screened axon guidance molecules by qRT-PCR, identified Ntn1 upregulation, and then verified its in vivo upregulation during pancreatic tumorigenesis in humans and mice. NTN1 and its receptor NEO1 were upregulated in epithelial cells by the Kras mutation and {beta}-adrenergic signaling, in part, through the MAPK pathway. Ex-vivo culture of celiac ganglia showed that NTN1 promoted the axonogenesis of sympathetic neurons through the nerve NEO1 receptor. In the Pdx1-Cre;LSL-KrasG12D/+ model, Ntn1 knockout decreased sympathetic innervation and the development of pancreatic intraepithelial neoplasia. Treatment of pancreatic tumor organoids with recombinant NTN1 enhanced cell growth, epithelial-mesenchymal transition (EMT), and cancer stemness with the upregulation of ZEB1 and SOX9 through NEO1-mediated activation of focal adhesion kinase (FAK). In Pdx1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+mice, Ntn1 knockout reduced innervation, FAK phosphorylation, and the features of EMT and stemness to extend mouse survival. In a liver metastasis model of PDAC (pancreatic ductal adenocarcinoma), treatment with a NTN1-neutralizing antibody or tumoral knockdown of Neo1 reduced ZEB1 and SOX9 and decreased tumor progression. In contrast, Ntn1 overexpression promoted innervation and the progression of PDAC liver metastasis. These data suggest that the NTN1/NEO1 axis is a key regulator of PDAC progression, directly influencing cancer cell stemness and EMT, while indirectly promoting tumor growth through nerves. Inhibiting the NTN1/NEO1 axis could represent a potential therapeutic approach for PDAC. Statement of SignificanceNTN1 promotes pancreatic tumorigenesis and metastasis directly and indirectly through nerves, highlighting the importance of tumor cell-nerve crosstalk in cancer. NTN1 blockade could represent a promising strategy for treating PDAC liver metastasis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/666009v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@ca611corg.highwire.dtl.DTLVardef@ad9264org.highwire.dtl.DTLVardef@1661c00org.highwire.dtl.DTLVardef@b86798_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Evaluation of the nano Liquid Chromatography coupled with Zeno TOF 7600 Mass Spectrometer for Cell Type-Resolved Spatial Proteomics

In this study, we systematically evaluated the nanoLC-Zeno TOF platform using data-independent acquisition (DIA) and identified 3,142 to 7,059 protein groups from 1 to 200 ng of standard K562 digest. Additionally, a targeted acquisition strategy detected 184 peptides with enhanced signal using Zeno activation. To achieve spatial cell-type resolved proteomics, we developed a workflow integrating image-guided laser capture microdissection for analysis of gastric cancer tissue. A 30-minute nanoLC gradient facilitated the quantification of 2,514 proteins from 0.2 mm{superscript 2} regions representing cancer cells, cancer-associated fibroblasts (CAFs), and immune cells, as defined by multiplex immunohistochemistry. This spatial proteomics approach revealed cellular heterogeneity within the tumor microenvironment of a clinical gastric cancer sample, and targeted validation identified differential expression of 12 cancer-associated proteins comprising 103 peptides between cancer cell-enriched and CAFs-enriched regions. This workflow offers a practical strategy for spatial visual proteomic analysis in clinical tissue samples.

cancer biology↗

bioRxiv2025

Features fusion or not: harnessing multiple pathological foundation models using Meta-Encoder for downstream tasks fine-tuning

The emergence of diverse pathological foundation models has empowered computational pathology tasks, including tumor classification, biomarker prediction, and RNA expression prediction. However, variations in model architecture and data sources lead to inconsistent downstream performance and complicate centralized training. Specifically, the lack of data sharing makes retraining foundation models with pooled data infeasible. Alternatively, the release of model parameters enables combining multiple models during fine-tuning. Inspired by the meta-analysis method, we propose the Meta-Encoder framework, which integrates features from multiple foundation models to generate a comprehensive representation, improving downstream fine-tuning task performance. Comparative experiments demonstrate that Meta-Encoder is more effective than individual foundation models, with its strengths more pronounced in handling complex tasks. While single models may perform sufficiently well for simple tasks, Meta-Encoder can match or even surpass the best-performing single model, alleviating concerns over model selection. Moderately challenging tasks benefit from Meta-Encoders concatenation or self-attention strategies, with the latter demonstrating superior performance in more challenging scenarios. For highly complex tasks, such as high-dimensional gene expression prediction, self-attention proves to be the most effective Meta-Encoder strategy, balancing feature integration and computational efficiency. For three patch-level spatial gene expression prediction tasks (HEST-Benchmark, CRC-inhouse, and Her2ST), the self-attention strategy improved the Pearson correlation by 38.58%, 26.06%, and 20.39%, respectively, compared to the average performance of three patch-level single models. Similarly, for the TCGA-BRCA, TCGA-NSCLC, and TCGA-CRC WSI-level bulk gene expression prediction tasks, the Pearson correlation increased by 14.36%, 9.27%, and 42.55%, respectively, compared to the average performance of two WSI-level single models. By leveraging multiple pathological foundation models using Meta-Encoder, it can further improve molecular characterization in pathology images to advance precision oncology.

bioinformatics↗

bioRxiv2025

A unified eIF1A+ luminal cells-centered hypoxic and "cold" tumor microenvironment promotes PCa progression among different subtypes

PCa is a malignancy with high heterogeneity arises from both tumor microenvironment (TME) and histological subtypes. To achieve superior clinical efficacy, it is imperative to identify unified progression drivers within such heterogeneity in PCa, thereby enabling the development of more consistent and effective therapeutic strategies. In this study, we applied imaging mass cytometry to stain 39 proteins on 71 tissues comprising para-cancer, low-grade acinar adenocarcinoma (LgPAC), high-grade PAC (HgPAC), intraductal carcinoma (IDC) and ductal adenocarcinoma (DAC) tissues, obtaining the spatial proteomic landscape of 345,233 single cells. We discovered a hypoxic eIF1A+ luminal epithelial (LE) cluster exhibiting both translational activation and immunosuppressive properties, which was enriched in high-risk PCa including HgPAC, IDC and DAC, and associated which tumor progression and unfavorable prognosis. Additionally, eIF1A+ LE orchestrates the formation of an immunologically "cold" TME, characterized by the low infiltration of anti-cancer immune cells including PD1- T cells CD163- macrophages. Through in vivo validation and investigator-initiated study, we further found that Homoharringtonine, an inhibitor targeting protein translation process, effectively inhibited PCa growth, alleviated hypoxic microenvironment, and enhanced immune cell infiltration. This study is the first to apply spatial proteomics to delineate consistent molecular features across histological subtypes, providing transformative insights for clinical management of PCa.

cancer biology↗

bioRxiv2025

Tff2 marks gastric corpus progenitors that give rise to pyloric metaplasia/SPEM following injury

In BriefTu et al. show that Tff2+ corpus isthmus cells are TA progenitors, and they, not chief cells, are the primary source of SPEM following injury. Upon Kras mutation, these progenitors directly progress to dysplasia, bypassing metaplasia, highlighting them as a potential origin of gastric cancer. HighlightsO_LITff2+ corpus cells are TA progenitors that give rise to secretory cells. C_LIO_LITff2+ progenitors, not chief cells, are the primary source of SPEM after injury. C_LIO_LIKras-mutant Tff2+ progenitors progress directly to dysplasia, bypassing metaplasia. C_LIO_LIMulti-omics analysis reveals distinct trajectories for SPEM and gastric cancer. C_LI O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/647847v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@48a2d1org.highwire.dtl.DTLVardef@b96642org.highwire.dtl.DTLVardef@1e89a4dorg.highwire.dtl.DTLVardef@1ea6a86_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG Pyloric metaplasia, also known as spasmolytic polypeptide-expressing metaplasia (SPEM), arises in the corpus in response to oxyntic atrophy, but its origin and role in gastric cancer remain poorly understood. Using Tff2-CreERT knockin mice, we identified highly proliferative Tff2+ progenitors in the corpus isthmus that give rise to multiple secretory lineages, including chief cells. While lacking long-term self-renewal ability, Tff2+ corpus progenitors rapidly expand to form short-term SPEM following acute injury or loss of chief cells. Genetic ablation of Tff2+ progenitors abrogated SPEM formation, while genetic ablation of GIF+ chief cells enhanced SPEM formation from Tff2+ progenitors. In response to H. pylori infection, Tff2+ progenitors progressed first to metaplasia and then later to dysplasia. Interestingly, induction of KrasG12D mutations in Tff2+ progenitors facilitated direct progression to dysplasia in part through the acquisition of stem cell-like properties. In contrast, Kras-mutated SPEM and chief cells were not able to progress to dysplasia. Tff2 mRNA was downregulated in isthmus cells during progression to dysplasia. Single-cell RNA sequencing and spatial transcriptomics of human tissues revealed distinct differentiation trajectories for SPEM and gastric cancer. These findings challenge the conventional interpretation of the stepwise progression through metaplasia and instead identify Tff2+ progenitor cells as potential cells of origin for SPEM and possibly for gastric cancer.

cell biology↗