Biology subjects

He, S.

Publications and source records attributed to He, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Disentangling motor and cognitive roles of cortical beta oscillations and their modulation with rTMS

Cortical beta oscillations are central to motor control. These rhythms are modulated during movement preparation and execution, and are also sensitive to cognitive factors such as uncertainty, attention and reward prediction. However, the distinct motor and cognitive roles of cortical beta oscillations --roles that may inform condition-specific therapeutic strategies--remain unclear. This study aimed to disentangle the respective contributions of motor and cognitive functions, and to assess their modulation with repetitive transcranial magnetic stimulation (rTMS). Twenty-four healthy participants performed a visually cued reaching task in which directional uncertainty was dynamically manipulated by varying the number of targets in real-time. Reaction time was quantified as a behavioural measure. Three stimulation conditions were applied during the preparatory periods between the uncertainty and go cues: no stimulation, regular rTMS at each participants individual beta frequency, and irregular rTMS. Electroencephalography was used to measure beta-band oscillatory activity. Our results showed that uncertainty cues induced bilateral beta suppression, with greater uncertainty linked to smaller reductions in beta power. Movement-related beta modulation was lateralised to the hemisphere contralateral to the executing hand, where elevated beta power in the pre- go cue period predicted longer reaction times. Both regular and irregular rTMS significantly shortened reaction times and attenuated beta event-related desynchronisation. Reductions in beta desynchronisation correlated with improvements in reaction times, suggesting beta desynchronisation reflects a neural threshold for movement initiation. These findings indicate that cortical beta oscillations encode distinct motor and cognitive processes, and that beta frequency rTMS can modulate beta dynamics to facilitate faster movement initiation by lowering this neural threshold.

neuroscience↗

bioRxiv2025

From deserts to forests: sequencing of the giant forest hog completes the genomic history of the African Suids

The giant forest hog (GFH, Hylochoerus meinertzhageni), the largest and most elusive wild pig, is found in a disjunct range across equatorial Africa, primarily inhabiting forests and woodlands. It is the only remaining African suid species without whole-genome data. The GFH is currently classified into three subspecies, differing in skull morphology and size. Here, we present the first whole-genome data of nine GFHs; one from Guinea and eight Uganda, representing the two geographically most distant subspecies. This genomic evidence allowed us to resolve the previously uncertain placement of the GFH among African suids as a sister group to the warthogs (Phacochoerus spp.). Also, we found a deep evolutionary split between the two GFH populations resulting in a level of genetic differentiation (FST > 0.75), which is similar to or higher than values observed among species of African wild pigs. The GFH likely diverged from warthogs around 4.6 Mya while the two study populations of GFH diverged at least 0.5 Mya and, subsequently, experienced very dissimilar demographic trajectories. The individual from Guinea had half of the heterozygosity level of the Uganda population, and lower value compared to all the African suids, probably as a result of the long term low Ne and isolation. Due to the close affinity of GFH with the African rainforest biotic zone, our findings have implications for understanding the history of habitat change in Africa. They also indicate a very deep and previously underappreciated evolutionary divergence within the GFH that may have implications for its conservation.

genomics↗

bioRxiv2025

TraN variants mediate conjugation species specificity of IncA/C, IncH and Acinetobacter baumannii plasmids

IncA/C and IncH plasmids commonly carry antimicrobial resistance genes, notably blaNDM-1. Although these plasmids disseminate among Gram-negative pathogens via conjugation, the mechanisms underlying mating pair stabilisation (MPS) and conjugation species specificity remain poorly understood. In IncF plasmids, MPS is mediated by interactions between outer membrane proteins (OMP) encoded by the plasmids in the donor (TraN) and by the chromosome in the recipient. Using the Plascad database, we extracted 1,436 TraN sequences: 62.5% (898/1,436), mainly in IncF plasmids, are 550-660aa (we renamed TraN short, TraNS); 15% (216/1,436), in IncA/C plasmids, are 880-950aa (TraN medium, TraNM); and 11% (160/1,436), in IncH plasmids, are 1,050-1,070aa (TraN long, TraNL). A group of six TraN from Acinetobacter baumannii plasmids (891aa) were designated TraN V-shaped (TraNV). Like TraNS, TraNM and TraNL contain base and distal tip domains essential for conjugation, whereas TraNV has a base and two distinct tip domains forming a V-shaped structure. TraNM, TraNL and TraNV determine conjugation species specificity, with TraNL cooperating with OmpA. Tip swapping reverses conjugation specificity, revealing how TraNM and TraNL diversity influence plasmid host range and AMR dissemination. Our new data reveal the molecular basis of plasmid host specificity and broaden our understanding of how conjugation drives the dissemination of antimicrobial resistance genes among clinically relevant bacteria.

microbiology↗

bioRxiv2025

StrainOptimizer empowers rational cell factory design through multi-scale metabolic models with expression and proteome constraints

The rational design of microbial cell factories for high bioproduction remains a key challenge in metabolic engineering. While advanced modelling frameworks incorporating protein resource allocation, such as enzyme-constrained models (ecGEMs) and Expression and Thermodynamic Flux (ETFL), provide superior predictive power, their application is limited by a lack of user-friendly computational tools. Here, we present strainOptimizer, a comprehensive computational platform for rational strain design that systematically evaluates key resource allocation principles: the coupling of gene expression with metabolism, subcellular compartmentalization, and enzyme capacity limitations. Our benchmark analyses demonstrate that each principle offers distinct advantages: models coupling metabolism and expression (like ETFL) enable the identification of non-metabolic targets, organelle-level proteomic constraints improve precision for high-protein-cost products, and protein-usage-based objectives consistently outperformed traditional flux-based approaches. To demonstrate its practical utility, we applied strainOptimizer to an engineered sclareol-overproducing Saccharomyces cerevisiae strain. The platform identified novel targets, and experimental validation confirmed a 67% success rate, increasing the final sclareol titer by 14-26% and productivity by up to 45%. StrainOptimizer bridges the gap between resource allocation theory and applied engineering, providing a powerful, validated tool to accelerate the development of high-performance cell factories.

bioengineering↗

bioRxiv2025

Integrated multi-omic and functional evidence uncover substantial strain-specific divergence in zebrafish

The zebrafish (Danio rerio) is a foundational vertebrate model in biomedical and developmental research, yet genetic divergence among laboratory strains remains an underappreciated source of biological and experimental variation. Among these, the AB and Tubingen (TU) strains are used globally, forming the basis for most zebrafish-based discoveries. Here, we integrated long- and short-read sequencing, ATAC-seq, Hi-C, transcriptomics, and functional assays to generate a comprehensive multi-omic comparison of these two strains. Our analyses revealed substantial genomic and regulatory divergence, including a 62-bp insertion in the asmt promoter that elevates transcription and alters melatonin biosynthesis, driving strain-specific circadian phenotypes. We also identify a non-synonymous variant (mybbp1aG2612C) associated with heightened immune responsiveness. Together, these findings construct the first genome-wide atlas of functional variation between zebrafish strains, illuminating how hidden genetic differences can shape phenotype, regulatory architecture, and experimental reproducibility in this essential vertebrate model.

genomics↗

bioRxiv2025

Ptf1a robustly drives the gliogenic switch in the rodent embryonic cortex in a dosage-dependent manner by activating pro-glial gene expression programs

It is widely believed that the gliogenic switch during rodent embryonic development is governed by the orchestrated crosstalk between a cohort of genes and extracellular cues. Here we report that ectopic expression of the single bHLH factor, pancreas transcription factor 1 (PTF1A), is sufficient to drive radial glial progenitors (RGPs)-regardless of progenitor heterogeneity and developmental stage-to differentiate into glial cells. Ptf1a- expressing RGPs exhibit progenitor behaviors indicative of a neurogenic-to-gliogenic fate transition, resembling endogenous progenitors at the late stages of embryonic development, and preferentially produce OLIG2+ oligodendrocytes in vivo, some of which are positive for PDGFR or CC1. This robust gliogenic competency depends on the dosage of stable Ptf1a expression in RGPs. RNAseq reveals the glial transcriptome, including upregulated expression of several notch signaling components and the endothelin receptors in Ptf1a RGPs. We further identify Ednrb as one of the downstream targets of Ptf1a that directs RGPs toward gliogenesis via the ERK1/2 signaling pathway. In summary, our study uncovers a novel and robust role for Ptf1a in glial fate specification, offering a potential strategy for generating human oligodendrocytes in vitro.

neuroscience↗

bioRxiv2025

Kinase KEY1 controls pyrenoid condensate size throughout the cell cycle by disrupting phase separation interactions

Biomolecular condensates spatially organize cellular functions, but the regulation of their size, number, dissolution, and re-condensation is poorly understood. The pyrenoid, an algal biomolecular condensate that mediates one-third of global CO2 fixation, typically exists as one large condensate per chloroplast, but during cell division it transiently dissolves and reconfigures into multiple smaller condensates. Here, we identify a kinase, KEY1, in the model alga Chlamydomonas reinhardtii that regulates pyrenoid condensate size and number dynamics throughout the cell cycle and is necessary for normal pyrenoid function and growth. Unlike wild type, key1 mutant cells have multiple smaller condensates throughout the cell cycle that fail to dissolve during cell division. We show that KEY1 localizes to the condensates and promotes their dissolution by disrupting interactions between their core constituents, the CO2-fixing enzyme Rubisco and its linker protein EPYC1, through EPYC1 phosphorylation. We develop a biophysical model that recapitulates KEY1-mediated condensate size and number regulation and suggests a mechanism for controlling condensate position. These data provide a foundation for the mechanistic understanding of the regulation of size, number, position, and dissolution in pyrenoids and other biomolecular condensates.

cell biology↗

bioRxiv2025

Demographic, behavioral, and ecological data from a long-term field study of wild baboons in Amboseli, Kenya

Long-term data sets on individually recognized animals and their environments are critical to understanding animal behavior, evolution, and ecology. However, they are resource- and time-intensive and seldom made publicly available. The Amboseli Baboon Research Project (ABRP) is one of the longest-running studies of a wild mammal population in the world and has collected extensive data on the baboon population of the Amboseli ecosystem in Kenya since 1971. Here, we describe four ABRP data sets newly available to the evolutionary biology, behavioral ecology, and primatology communities: (1) the sizes and demographic compositions of 21 social groups from 1971-2023; (2) the activity budgets of adult females and immatures from 1984-2023; (3) behavioral data on diet for adult females and immatures from 1984-2023; and (4) weather data, including precipitation from 1976-2023 and temperature from 1976-2022. Data are aggregated annually and monthly to enable cross-data set analyses. These data offer a rare longitudinal perspective on behavioral and ecological change in a wild mammal population.

animal behavior and cognition↗

bioRxiv2025

Dithering suppresses half-harmonic neural synchronisation to photic stimulation in humans

While entraining neural rhythms using brain stimulation has been suggested as a therapeutic mechanism to normalise brain activity in conditions such as depression, chronic pain, or Alzheimers disease, periodic stimulation can also inadvertently entrain brain rhythms at sub- and superharmonics of the stimulation frequency, which could lead to deleterious effects. Slightly jittering stimulation pulses (called "dithering") was previously proposed on the basis of mathematical modelling to selectively entrain a target neural rhythm while avoiding harmonic entrainment. In this study, we investigated the potential of dithering in humans. Using photic stimulation (light flicker) and EEG recordings in healthy participants, we showed that dithering suppresses half-harmonic synchronisation relative to perfectly periodic flicker, and more so than synchronisation at the stimulation frequency. This was also the case for a periodic condition with reduced stimulation amplitude, as predicted by theory. Furthermore, we demonstrated using synthetic data and modelling that the half-harmonic responses observed in participants cannot be explained by the super-position of evoked responses (even when modulated at the half-harmonic frequency), and are better matched by a minimal oscillator model. Our findings are consistent with half-harmonic EEG synchronisation in response to photic stimulation predom-inantly reflecting half-harmonic entrainment rather than the summation of evoked responses, and with dithering being an effective strategy to suppress subharmonic entrainment.

neuroscience↗

bioRxiv2025

RNAcentral in 2026: Genes and literature integration

RNAcentral was founded in 2014 to serve as a comprehensive database of non-coding RNA sequences. It began by providing a single unified interface to more specialised resources, and now contains 45 million sequences. It has grown beyond providing a single interface to many specialised resources and now provides several services and analyses. These include secondary structure prediction with R2DT, sequence search, and analysis with Rfam. Since its last publication in 2021, RNAcentral has developed two major features. First, literature integration with the development of LitScan and LitSumm. LitScan automatically identifies and links relevant publications to RNA entries, while LitSumm uses natural language processing to generate functional summaries from the literature. Together, these tools address the critical challenge of connecting sequence data with scattered functional knowledge across thousands of publications. Secondly, RNAcentral has created gene level entries. Gene level entries represent a large structural change to RNAcentral. While RNAcentral previously organized data exclusively at the sequence level, we now group related transcripts into gene-centric views. This allows researchers to explore all isoforms, splice variants, and related sequences for a gene in a unified interface, better reflecting biological organization and facilitating comparative analyses. RNAcentral is freely available at: https://rnacentral.org.

bioinformatics↗

bioRxiv2025

Chromosomal Restructuring and Subgenome Divergence Drive Post-Polyploid Adaptive Diversification in Sinocyclocheilus Cavefish

Allopolyploidy generates extensive genomic potential, yet its role in adaptive diversification remains poorly understood. We assembled phased chromosome-level genomes of cave and surface ecotypes of Sinocyclocheilus, a rapidly diversifying cavefish lineage, the most species-rich in the world. Our analyses show that all species derive from the ancestral allotetraploidisation event common to all cyprinids without subsequent polyploidisation. Instead, diversification has been driven by chromosomal rearrangements and the emergence of subgenome asymmetry. The dominant D subgenome maintains more genes, exhibits higher expression, and is enriched for adaptive functions, while the submissive S subgenome is inclined towards housekeeping roles. This asymmetry is further reinforced by the accumulation of transposable elements near genes exhibiting expression biased toward the S-subgenome. We also identify a derived epigenetic mechanism in the cave ecotype, i.e., differential methylation of these elements, absent in the surface ecotype. These findings show how structural, regulatory, and epigenetic processes have interacted following allopolyploidy to produce ecological and phenotypic diversity in Sinocyclocheilus. Our findings also offer quantitative evidence that cave adaptation is a complex process characterised by an evolutionary trade-off - the regression of energetically expensive traits combined with the remodeling of neural and developmental pathways driven by natural selection.

evolutionary biology↗

bioRxiv2025

Water body size shapes body size evolution via subgenomic selection in allopolyploid fish

Allopolyploidization is a major force in species evolution, and studying allopolyploids in diverse environments provides insights into their genetic mechanisms. Here, we investigated how water body size variation influences body size in allopolyploid fish. We used a nascent allopolyploid lineage derived from goldfish (Carassius auratus) and common carp (Cyprinus carpio) and established two populations in small and large water bodies for two generations. Genomic, transcriptomic, and epigenomic analyses revealed that the larger population had higher genetic diversity in subgenome R, while the smaller population had higher diversity in subgenome C. Potential selection regions were associated with growth regulatory genes, suggesting a role for gene regulation in body size adaptation. Dynamic gene expression patterns in various tissues indicated potential mechanisms underlying muscle development and adaptation to smaller water bodies. Furthermore, selection regions were linked to changes in chromatin accessibility, with subgenome R being more susceptible to these changes during genetic divergence. Our findings demonstrate that water body size variation drives body size in allopolyploid fish through subgenomic selection, impacting genetic variation, gene regulation, and epigenetic mechanisms.

genomics↗

bioRxiv2025

LRH-1 is a novel regulator of neutrophil-driven immune responses within the tumor microenvironment.

Elevated plasma cholesterol levels have been linked to worse outcomes in breast and ovarian cancer. Prior work including our own has demonstrated that myeloid immune cells are highly responsive to cholesterol fluctuations and to proteins involved in cholesterol regulation. However, the specific roles of Liver Receptor Homolog-1 (LRH-1, or NR5A2), a key transcriptional regulator of cholesterol homeostasis, within myeloid cells remains largely undefined. Interestingly, LRH-1 mRNA levels are reduced in both breast and ovarian tumors compared to normal tissue. Its elevated expression within tumors is associated with increased survival time. These clinical correlations prompted us to explore the role of LRH-1 in myeloid cells particularly in the context of breast and ovarian cancer progression. Initial analyses confirmed LRH-1 expression in various myeloid cell types, with particularly high levels in neutrophils. We therefore focused on how LRH-1 influences neutrophil behaviors relevant to cancer, including migration, NETosis, phagocytosis, and interactions with T cells. Small molecule ligands for LRH-1 regulated neutrophil migration towards cancer cells. Phagocytosis was also regulated by LRH-1 small molecule ligands, the extent being dependent on type of bait (e. coli vs. cancer cells). In T cell co-cultures, neutrophils pretreated with an LRH-1 agonist promoted greater T cell expansion - particularly in CD4 cells - while LRH-1 inhibition suppressed this response. Moreover, LRH-1 activation reduced NETosis, while treatment with an antagonist or inverse agonist enhanced NETosis. Treatment of mice with an inverse agonist of LRH-1 increased the growth of 4T1 and E0771 mammary tumors. Given prior evidence that neutrophils contribute to the recurrence of dormant lesions, we further examined the role of LRH-1 in this context. Mice harboring dormant D2.0R mammary cancer lesions treated with an LRH-1 inverse agonist exhibited earlier tumor recurrence and enhanced metastatic progression compared to vehicle-treated controls. In contrast, treatment with BL001, a small chemical LRH-1 agonist, delayed recurrence in D2.0R-grafted mice. Collectively, these findings reveal that LRH-1 is a novel regulator of neutrophil-driven immune responses within the tumor microenvironment. LRH-1 thus remerges as a promising therapeutic target to suppress metastasis or prevent recurrence in breast cancer.

cancer biology↗

bioRxiv2025

SPACE: spatially resolved multiomic analysis for high-throughput CRISPR screening in 3D models

Current spatial CRISPR screening technologies are limited by targeted readouts and high costs, restricting the scope of biological discovery. Here we present SPAtial Cell Exploration (SPACE), a spatial CRISPR screening platform that integrates whole-transcriptome profiling ([~]18,000 genes), multiplexed protein detection ([~]68 markers), and CRISPR perturbation mapping at subcellular resolution. SPACE significantly reduces whole-transcriptome profiling costs compared to sequencing methods while preserving spatial context. We demonstrate SPACE by screening 43 CRISPR knockouts (KOs) across [~]100,000 cells in hundreds of cancer-associated fibroblast (CAF)-tumor spheroids, obtaining whole-transcriptome and multiplexed protein readout from the same exact cells. SPACE revealed previously unknown regulatory mechanisms on tumor extracellular matrix (ECM) remodeling, and identified spatially-resolved ligand-receptor interactions and perturbation-specific spatial gene signatures that are not detectable with dissociation-based methods. This scalable, cost-effective platform provides a transformative framework for high-throughput spatial perturbation studies in complex tissue models.

cell biology↗

bioRxiv2025

Universal principles of protein resource allocation among cellular organelles revealed by yeast large-scale absolute quantitative proteomics

The presence of organelles is a hallmark distinguishing eukarya from bacteria and archaea, and this culminates in compartmentalization of cellular metabolism and subsequent metabolic specialization. Here we established a dataset encompassing over 300 absolute quantitative proteomes, the largest to date, across two yeast species under diverse experimental conditions. Leveraging big data analysis, formula fitting, and machine learning models, quantitative correlations among protein abundance, organelle-level resource distribution, and cellular phenotypes were elucidated at a system level. We found that protein resources always exhibit robust and precise distribution at the organelle level across distinct conditions. Specifically, at high specific growth rates, the protein mass fraction from some main organelles, i.e., peroxisome and nucleus, is consistently reduced to offset the increasing protein resource demand from the ribosome. Meanwhile, we found that the nutrition limitation could induce resource recycling by upregulating protein resources within the vacuole and lipid droplets to sustain stress adaptation. Importantly, our integrative analysis demonstrates that protein mass fraction from less than 4 organelles (e.g., nucleus and ribosomes) can accurately predict diverse yeast physiological parameters (e.g., specific growth rate, oxygen uptake rate), and a core set of 37 proteins could predict resource allocation among 24 main organelles and sub-organelles with high accuracy (average R^2 > 0.9). Finally, we found organelle resource allocation reflects the divergence of yeast species. For example, anaerobic conditions and respiratory suppression have less influence on Crabtree-positive yeast, i.e., Saccharomyces cerevisiae, with respect to organelle resource allocation but have a larger effect on the Crabtree-negative yeast Issatchenkia orientalis, thus suggesting that cellular resources have facilitated adaptive evolution. In summary, the high-quality, genome-scale quantitative proteomic dataset for yeast species offers an unprecedented opportunity for understanding the basic principles underlying resource allocation at the organelle level, laying theoretical foundations for precision engineering of cell factories in synthetic biology. The resource used in this study is available at https://yeast-proteome-database.streamlit.app/.

systems biology↗

bioRxiv2025

Single-vessel transcriptome map pathological landscapes and reveal NR2F2-mediated smooth muscle cell phenotype acquisition in capillary malformations

BackgroundCapillary malformation (CM) is a congenital vascular anomaly affecting the skin, mucosa, and brain, yet the understanding of its vascular pathogenesis remains limited. MethodsWe applied spatial whole-transcriptome profiling (GeoMx) and gene set enrichment analysis within CM lesions at single vasculature level. Differentially expressed genes were validated by immunofluorescence staining. Phosphoproteomics was profiled to uncover lesion- wide phosphorylation sites on proteins. Single-cell RNA sequencing was performed on CM- derived induced pluripotent stem cells (iPSCs) to determine differentiation trajectories of lesional vascular lineages. In silico gene perturbation was used to predict candidate genes for modulating vascular pathological progression, followed by functional validation in CM iPSC-derived endothelial cells (ECs) using a Tet-on system. ResultsA spatial transcriptomic atlas was constructed, and pathological landscape of individual CM vasculature was delineated. CM vessels exhibited hallmarks of endothelial-to-mesenchymal transition (EndMT), including disruption of adherens junctions (AJs), vascular identity transitions, and metabolic remodeling. Phosphoproteomics confirmed that differentially phosphorylated proteins were enriched in EndMT- and AJ-related pathways. Aberrant expression of venous transcriptional factor NR2F2 was observed in lesional ECs and correlated with progressive enlargement from capillaries to larger-caliber vessels containing multiple layers of smooth muscle cells (SMCs). In CM iPSCs, differentiation course yielded reduced ECs but increased SMCs. In silico knockout simulation predicted NR2F2 as a crucial regulator of facilitating SMC phenotype in CM. Consistently, enforced NR2F2 expression during iPSC differentiation suppressed endothelial markers while inducing SMC-associated genes. ConclusionsSingle CM vasculature displays pathological hallmarks characterized by EndMT and AJ disruption, leading to progressive vascular remodeling. NR2F2 functions as a central regulatory factor orchestrating the acquisition of the SMC phenotype, thereby representing a potential therapeutic target in CM.

pathology↗

bioRxiv2025

Ergothioneine and a new food supplement product protectagainst cyclophosphamide-induced premature ovarianfailure in rats

Premature ovarian failure (POF) is characterized by disrupted estrous cycles and impaired folliculogenesis due to oxidative stress and inflammation. In this study, a cyclophosphamide (CTX)-induced POF rat model was used to evaluate the protective effects of ergothioneine (EGT) and a nutraceutical formula (FineNutri Cellular Vitality Capsules) containing EGT. CTX treatment markedly prolonged the estrous cycle, reduced estrus duration, decreased ovarian weight, impaired follicular development, and increased granulosa cell apoptosis. Serum estradiol (E2) and anti-Mullerian hormone (AMH) levels decreased, whereas luteinizing hormone (LH) and follicle-stimulating hormone (FSH) increased, reflecting disruption of the hypothalamic-pituitary-ovarian axis by CTX. CTX treatment induced oxidative stress, with reduced catalase (CAT), superoxide dismutase (SOD) activity, and glutathione (GSH) content, and increased malondialdehyde (MDA) in ovarian tissue. The EGT and the nutraceutical formula restored estrous cycles, increased ovarian weight, improved primordial follicle counts, and reduced atretic follicles and granulosa cell apoptosis. Hormonal balance was partially restored, with increased E2 and AMH and reduced LH and FSH levels. Oxidative stress was alleviated with higher CAT, SOD, and GSH levels and reduced MDA concentrations. In addition, EGT and the formula reduced inflammation in skin tissue. These findings suggest that EGT and the nutraceutical formula could protect against CTX-induced POF and help preserve ovarian function, probably by mitigating oxidative stress.

pharmacology and toxicology↗

bioRxiv2025

The Pdgfd-Pdgfrb axis orchestrates tumor-nerve crosstalk in pancreatic cancer

Nerves are an integral component of the tumor microenvironment, contributing to cancer progression, metastasis, morbidity, and mortality. In pancreatic ductal adenocarcinoma (PDAC), worse clinical outcomes are associated with perineural invasion (PNI), a process by which cancer cells surround and invade nerves. Here, we employed whole-transcriptome and single-cell spatial transcriptomics to identify candidate tumor-nerve interactions that promote PNI. We discovered that Pdgfd signaling promotes key features of nerve invasion. Mechanistically, Pdgfd stimulated cancer cell invasiveness, neurite outgrowth, and direct physical engagement with glia. Pharmacological blockade of this axis reduced each of these processes in vitro as well as PNI in vivo. Thus, Pdgfd-Pdgfrb signaling mediates PNI by coordinating multifaceted cancer-neuron-glia interactions and represents a promising therapeutic strategy aimed at disrupting harmful cancer-nerve crosstalk.

cancer biology↗