Biology subjects

Zhuang, X.

Publications and source records attributed to Zhuang, X..

At least 19 recordsLinked to original sources

bioRxiv2026

MERFISH-based pooled genetic screening reveals cell non-autonomous phenotypes in intact tissue

Genetic perturbations can reshape both the state of a targeted cell and the behavior of neighboring cells. Measuring these effects systematically in intact tissues requires pooled screening methods that jointly identify perturbations, molecular phenotypes, and spatial context of individual cells. Here, we report an imaging-based pooled screening method that detects perturbation identities and endogenous RNAs without enzymatic amplification. Relative to our previous enzymatic-amplification-based workflow, amplification-free MERFISH detection with direct hybridization increased recovery of perturbation barcodes by ~10-fold and endogenous transcripts by 2.5-fold, improving perturbation assignment as well as molecular profiling of both perturbed and neighboring cells. Applying this method to a genetic mosaic mouse liver screen targeting ~200 genes in hepatocytes, we profiled 1.5 million cells in intact tissues and mapped both cell-autonomous responses of perturbed hepatocytes and cell non-autonomous changes in neighboring immune and vascular populations. These included localized accumulation of pDC-like cells near hepatocytes with impaired V-ATPase function and angiogenic responses in vascular cells near Vhl-perturbed hepatocytes with hypoxia activation. Our method provides a simplified, scalable approach to linking genetic perturbations with cell state, multicellular response, and tissue organization.

genomics↗

bioRxiv2026

Arabidopsis BAG proteins regulate cellulose synthase stability

Cellulose synthase complexes (CSCs) synthesize cellulose at the plasma membrane, and their activity and trafficking are critical for maintaining cell wall integrity during plant growth. Clathrin-mediated endocytosis (CME) regulates CSC internalization and has been implicated in their rapid stress-induced removal from the plasma membrane. Stress adaptation, instead, requires the maintenance of a subset of CSCs at the plasma membrane, yet the mechanisms underlying this homeostasis remain poorly understood. The Arabidopsis Bcl-2-associated athanogene4 (BAG4) was identified as an interactor of the adaptor protein 2 complex (AP-2) and the TPLATE complex (TPC), two key components of plant CME. Here, we show that AP-2 and the TPC associated with four closely related BAG proteins, BAG1-BAG4. A quadruple mutant exhibited abnormal growth, increased sensitivity to salt stress, and reduced endocytic flux. However, the abundance, localization and dynamics of CME machinery was largely unaffected, suggesting that BAG proteins are not core regulators of CME. Instead, BAG1-BAG4 deficiency caused hypersensitivity to cellulose biosynthesis inhibitors and impaired hypocotyl elongation in darkness, consistent with defective cellulose-dependent growth. BAG1-BAG4 also interacted with CESA6, and salt-induced CESA6 degradation and ubiquitination was enhanced in the quadruple mutant. Together, these findings identify BAG1-BAG4 as redundant proteostasis factors that safeguard CESA6 stability during salt stress, thereby maintaining cellulose synthesis, cell wall integrity, and plant stress tolerance.

plant biology↗

bioRxiv2026

Association of object mnemonic discrimination deficit with age and AD biomarkers in older adults

Background Blood-based Alzheimers disease (AD) biomarkers provide scalable detection of AD pathology, yet their relationships with hippocampal-dependent mnemonic discrimination remain unclear. This study examined how object mnemonic discrimination relates to age, hippocampal structure, and plasma AD biomarkers in cognitively normal (CN) older adults and individuals with amnestic mild cognitive impairment (aMCI). Methods Forty-six CN and forty-one aMCI participants completed an object mnemonic similarity task (MST). Mnemonic discrimination was quantified using the overall lure discrimination index (LDI) and similarity-specific LDIs. Plasma pTau181, pTau217, pTau231, and GFAP were assayed, and hippocampal volumes were derived from 7T MR scanner. Multiple linear regression models assessed associations between LDI and biomarkers, controlling for age, sex, education, APOE4 status, and diagnosis. Repeated-measures ANCOVA and linear mixed-effects models evaluated similarity-dependent age effects. ROC analyses and stepwise logistic regression quantified diagnostic classification performance. Results LDI was significantly reduced in aMCI compared to CN. Total hippocampal volume and plasma pTau217 showed the strongest associations with LDI, exceeding those of pTau181, pTau231, and GFAP. LDI discriminated aMCI from CN with high accuracy (AUC = 0.836), comparable to hippocampal volume and plasma biomarkers. A combined model including LDI, pTau181, pTau217, and hippocampal volume achieved the highest diagnostic accuracy (AUC = 0.931). Age effects were similarity-dependent: discrimination declined with age only for low-similarity lures, independent of diagnosis. Sex differences emerged within aMCI, with females showing lower LDI than males. Conclusions Object mnemonic discrimination provides a sensitive behavioral marker linked to hippocampal volume and plasma pTau217, showing discriminative power comparable to established AD biomarkers in separating aMCI from CN participants. Similarity-dependent age effects highlight age-related deficits are not universal for lures with varying similarity levels.

neuroscience↗

bioRxiv2026

A recombinant dilp2GS-rpr donor line for adult-inducible IPC ablation across Drosophila genetic backgrounds

Genetic-background studies require defined perturbations that can be crossed reproducibly into many recipient backgrounds. We generated a Drosophila dilp2GS-rpr donor line for adult-inducible ablation of insulin-producing cells (IPCs), which secrete insulin-like peptides and provide a tractable model of insulin-deficient metabolic physiology. This line carries dilp2-GeneSwitch-GAL4 and UAS-reaper in cis on the same second chromosome homolog over a balancer. PCR genotyping and sequencing confirmed both transgenic elements in the candidate recombinant line. RU486 induction reduced dilp2 mRNA expression, supporting partial IPC ablation. Treatment-duration testing identified 8 days of RU486 as sufficient to increase whole-body glucose in the dilp2GS-rpr line but not in the background-matched control; food intake did not differ between RU486- and vehicle-treated flies. Across metabolic assays, whole-body glucose showed the clearest RU486- and line-dependent phenotype. This validated dilp2GS-rpr line enables testing how recipient genetic backgrounds modify inducible IPC/DILP metabolic phenotypes and provides a framework for similar linked donor-line resources.

genetics↗

bioRxiv2026

ROS Impair Mitophagy via PARylation of PINK1

Mitophagy is the process of selective autophagic clearance of damaged mitochondria and is closely implicated in neurodegenerative disease. PTEN-induced kinase 1 (PINK1) and a RBR E3 ubiquitin-protein ligase (Parkin) constitute a positive feedback loop in mitophagy initiation. It is known that reactive oxygen species (ROS) modulate mitophagy, while the exact regulatory mechanism remains largely elusive. Here, we found that exogenously applied ROS effectively block mitophagy induced by acute mitochondrial damage agents, which could be reversed by antioxidants. Mechanistically, ROS activate poly(ADP-ribose) polymerase 1 (PARP1), and suppression of PARP1 eliminates the inhibitory effect of ROS on mitophagy. Notably, PARP1 directly interacts with PINK1 and mediates its PARylation at residue E417, thereby negatively regulating PINK1 function. Collectively, our study identifies PARylation as a new form of post-translational modification of PINK1 and reveals a novel mechanism underlying the regulatory role of ROS in mitophagy by PARP1 activation and PARylation of PINK1. In briefGao et al. demonstrate that exogenous ROS inhibit mitophagy. Mechanistically, ROS activate PARP1, which mediates PARylation of PINK1, a central regulator of mitophagy, leading to its functional impairment. This study reveals a novel regulatory mechanism of ROS on mitophagy through PARP1 activation and identifies PARylation as a novel form of post-translational modification of PINK1. HighlightsO_LIROS block PINK1-Parkin-mediated mitophagy. C_LIO_LIROS activate PARP1. C_LIO_LIPARP1 suppression eliminates the inhibitory effect of ROS on mitophagy. C_LIO_LIPARylation of PINK1 by PARP1 impairs its activity and mitophagy. C_LI

Cell Biology↗

bioRxiv2026

Outbred Drosophila populations reveal diet-dependent genetic effects on development time

Metabolic effects of genetic variation often depend on diet, yet the loci underlying diet-dependent developmental responses remain incompletely defined. Here we combine multi-trait phenotyping of Drosophila Genetic Reference Panel lines with genome-wide mapping in newly developed Drosophila Recombinant Populations. High sugar causes genotype- and life-stage-dependent changes in metabolic and life-history traits, with development time emerging as a highly heritable, sugar-sensitive phenotype. Mapping in 16 outbred advanced intercross populations reveals distinct association landscapes under low- and high-sugar diets, with a concentrated low-sugar signal, a more distributed high-sugar pattern, and identified genotype-by-diet loci including tap, Eip75B and Cerk. Functional perturbation supports diet-dependent effects for several prioritized candidates. Allele-frequency analyses identify operationally defined thrifty-like variants associated with delayed development under high sugar and relatively earlier development under low sugar; these variants are enriched for cell-adhesion, neurodevelopmental, and morphogenetic processes. Together, these results establish an outbred Drosophila framework for dissecting how dietary sugar remodels the genetic architecture of development time.

genetics↗

bioRxiv2026

Gene loss under constant cold reveals "natural knockout" loci in Antarctic notothenioid fishes

BackgroundGene loss is a major but often underappreciated mode of genome evolution. Genes loss can reflect relaxed selective constraint, neutral decay, compensation, or adaptive change; once fixed, however, they alter the inherited gene complement and can shape the evolutionary trajectories available to descendant lineages. Shared losses near the base of a radiation may therefore become part of the genomic background on which later specialization occurs. The Antarctic notothenioid (cryonotothenioid) radiation provides a powerful system for studying gene loss in an extreme polar environment: it diversified in the thermally stable Southern Ocean, and outgroups outside the clade allow ancestral gene presence to be inferred. ResultsUsing whole-genome alignments and orthology-aware comparative analyses across 11 cryonotothenioids and four non-Antarctic notothenioid outgroups, we systematically identified gene-inactivating mutations and reconstructed their phylogenetic distribution. After applying stringent filters to reduce reference bias, mitigate assembly and annotation artifacts, and exclude loci with detectable transcriptomic support, we identified 30 high-confidence single-copy orthologs with loss of coding potential across sampled cryonotothenioids but intact coding sequences in outgroups. These clade-wide losses affect genes associated with lipid and amino acid metabolism, water transport, renal glucose reabsorption, skeletal mineralization, circadian regulation, and tRNA modification pathways. We also identified 12 additional single-copy orthologs lost across examined icefishes but retained in red-blooded notothenioids and outgroups, including genes associated with oxygen transport, iron handling, erythroid biology, and vesicular trafficking. ConclusionsOur study provides a genome-wide catalog of coding-gene losses shared across sampled cryonotothenioids, together with additional lineage-specific losses in icefishes. Many of these losses occur in conserved genes associated with disease-relevant phenotypes in humans or model vertebrates, suggesting that Antarctic notothenioids offer a natural comparative system for studying how loss-of-function variants can persist in viable wild populations. These candidate natural knockouts provide testable hypotheses for how environmental buffering, paralog compensation, and pathway rewiring may shape vertebrate physiology under chronic cold.

genomics↗

bioRxiv2026

Global cell-state and gene-program representations reveal conserved and context-specific perturbation responses of cells

Understanding how cell states change in response to genetic perturbations is critical for gene-function and therapeutics discovery. However, state-of-the-art deep-learning models trained on large single-cell omics datasets still struggle to accurately predict cellular responses to perturbations, highlighting the need for a better understanding of the cell-state space and how cells move through this space. Here, we present a contrastive learning model that integrates diverse scRNA-seq datasets into a global, interpretable cell-state manifold. We further develop a framework to integrate this global cell-state manifold with genome-scale perturbation data to identify gene-expression programs that define principal axes of cell-state transitions and functional embeddings of genes that define major perturbation classes. Applying this framework across Perturb-seq datasets on different cell types reveals conserved cellular responses to perturbations, as well as cell-type-specific rewiring of stress responses. Moreover, we perform a genome-scale Perturb-seq screen in human embryonic stem cells, validating and extending these findings and uncovering a class of mesenchymal transitions induced by diverse perturbations to cellular stress-response pathways.

systems biology↗

bioRxiv2026

Comprehensive Lineage Tracing Maps the Landscape of Cell Fate Decisions in Mouse Embryogenesis

A comprehensive cell fate map of mammalian embryogenesis has remained out of reach due to the scale, cellular diversity, and non-deterministic nature of development in utero. Here, we use PEtracer to continuously install heritable genetic marks as cells divide, reconstructing lineage trees that resolve [~]75% of cell divisions across >1.5 million cells from 16 mouse embryos collected at half-day intervals from E7.5-E10.0. We pair these trees with deep transcriptional profiling to chart the landscape of cell fate decisions during gastrulation and early organogenesis. Using these data, we quantify cell fate biases, restriction timing, progenitor pool sizes, and lineage relationships across the embryo, revealing strikingly reproducible lineage architecture across replicate embryos despite the regulative flexibility of mammalian development. We further show how lineage, spatial position, and signaling jointly determine fate outcomes and timing, with their relative influence varying by tissue. This dataset provides a quantitative framework for understanding cell fate specification and a lineage-resolved reference for generating and contextualizing developmental hypotheses at organismal scale.

developmental biology↗

bioRxiv2026

Transposable Elements Facilitate the De Novo Origin of Antifreeze Protein and the Diversification of Its Gene Family in Snailfishes

Transposable elements (TEs) are increasingly recognized as important sources of genomic innovation, yet mechanistically resolved examples of how they help generate new functional genes in vertebrates remain rare. Type I antifreeze proteins (AFPI) in fishes are life-saving adaptations shaped by strong freezing selection and provide an exceptional system for studying new gene evolution under extreme environmental pressure. We recently showed that AFPI in flounder, cunner, and sculpin evolved independently through distinct partial de novo routes, converging on a nearly identical alanine-rich antifreeze protein. Here, we elucidate the origin and evolution of AFPI in the last remaining unresolved lineage, snailfishes, using a chromosome-scale genome assembly for Liparis atlanticus together with multi-tissue Iso-Seq, tissue-specific RNA-seq, and comparative genomics across AFPI-bearing and AFPI-lacking snailfishes and teleost outgroups. We show that snailfish AFPI originated within Liparis and rapidly diversified as a young gene family with multiple isoforms and lineage- and population-specific copy-number change. Genome-wide homology searches support a de novo origin of the alanine-rich coding region from noncoding sequence rather than from a pre-existing protein-coding precursor. In contrast, the surrounding regulatory architecture was assembled through sequence recruitment: a hAT-derived fragment contributes promoter- and transcription-start-site-proximal sequence, and a conserved noncoding segment together with a Ty3/Gypsy-derived long terminal repeat (LTR) contributes the 3' regulatory region. TE-rich locus structure also provides plausible mechanisms for subsequent locus expansion and translocation. Together, these results reveal a TE-facilitated, mosaic route to new gene evolution in vertebrates, demonstrating how noncoding DNA, repetitive sequence, and TE-derived regulatory fragments can be assembled into a strongly selected adaptive innovation. Author SummaryWhere do new genes with brand-new functions come from? We tackled this question using one of evolutions clearest natural experiments: antifreeze proteins, life-saving molecules favored by selection because fish without them freeze in icy seawater. In this study, we show that mobile DNA called transposable elements helped build a new antifreeze gene in stages. Different transposable elements appear to have played different roles: one helped switch on a previously silent stretch of noncoding DNA, others contributed control sequences at the beginning and end of the gene, and repeat-rich DNA around the locus likely promoted gene duplication, movement to a new chromosomal location, and rapid diversification into a gene family. This is an unusually clear vertebrate example of how a new gene can emerge not in a single leap, but through stepwise assembly from different pieces of the genome. More broadly, our work shows that transposable elements do much more than disrupt genomes. Under strong natural selection, they can help turn noncoding DNA into a life-saving adaptation and then help that innovation expand and diversify.

genetics↗

bioRxiv2026

Disruption of Drosophila melanogaster Larval Locomotion Caused by Silver Ions

Silver (Ag+) ions are known to be toxic to bacteria, cells, organisms and living systems; yet its impacts on the locomotion of surface-crawling organisms remain poorly quantified. Here we investigated the short-term (0-6 hours) effects of Ag+ ions on the locomotion of Drosophila melanogaster larvae on flat agarose surfaces containing Ag+ ions at different concentrations (0, 1, 10, and 100 mM). By quantifying their locomotion, we found that Drosophila larvae showed shorter accumulated distances and reduced crawling speed. Additionally, we quantified the go/stop dynamics and peristalsis of the larvae and observed that Ag+ ions disrupted the normal, rhythmic, peristaltic contraction of the larvae and "trapped" them in the stop phase. Such toxic effects were dependent on Ag+ concentration and exposure duration.

biophysics↗

bioRxiv2026

Starvation-induced autophagy occurs independently of the ATG1 complex in Chlamydomonas

The survival of eukaryotes during starvation depends on effective nutrient recycling via autophagy. Accordingly, loss of autophagy-related (ATG) proteins, including the nutrient-sensing ATG1 kinase complex, typically results in reduced fitness or lethality under nutrient limitation. The green alga Chlamydomonas reinhardtii provides a tractable model for autophagy studies, as its ATG repertoire is encoded by single-copy genes. Here, we generated a comprehensive library of ATG deletion mutants and examined their growth and autophagy during starvation. Surprisingly, starvation-induced autophagy occurred in the absence of ATG1 complex components (ATG1, ATG11, ATG13, and ATG101), revealing ATG1-independent autophagy and challenging the canonical model for autophagy initiation.

molecular biology↗

bioRxiv2026

Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer

Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune-checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.

cancer biology↗

bioRxiv2025

Age-varying DNA methylation patterns associated with blood pressure across the lifespan

BackgroundEpigenome-wide association studies (EWAS) have identified associations between DNA methylation and blood pressure, yet most rely on single-time-point data and cannot capture how methylation and blood pressure relationships change with age. MethodsWe conducted a longitudinal EWAS of 1,945 blood samples from 976 participants in the Multi-Ethnic Study of Atherosclerosis using a spline-based varying-coefficient model to detect age-dependent associations between DNA methylation in blood and blood pressure traits. Findings were evaluated for replication in 1,187 samples from the Framingham Heart Study. Models were adjusted for sex, ancestry, and leukocyte composition to account for cellular heterogeneity. ResultsSix CpG sites showed significant age-dependent associations with systolic or pulse pressure after correction for multiple testing. These included loci within STIP1, CSRP1, and KDM6A that replicated in the Framingham cohort. Several CpG sites demonstrated a reversal of effect direction with advancing age, where higher methylation was associated with higher systolic pressure in younger adults but lower pressure later in life. Pathway enrichment analyses identified focal adhesion, actin cytoskeleton remodeling, and Wnt/{beta}-catenin signaling, which are processes relevant to vascular aging. Drug target mapping identified 23 FDA-approved agents interacting with genes at these loci. ConclusionsBlood-derived DNA methylation shows dynamic age-related associations with blood pressure that likely reflect systemic or vascular aging processes rather than direct cellular mediation. Longitudinal analytical frameworks can reveal temporal patterns in epigenetic variation that are not detectable in single time point studies and may inform the discovery of biomarkers for age related cardiovascular risk.

genetics↗

bioRxiv2025

Targeting Macrophage Folate Receptor-β for Diagnosis and Treatment of Autoimmune Myocarditis

We investigated folate receptor-{beta} (FR-{beta}) expressed on activated macrophages as a therapeutic and imaging target in autoimmune myocarditis (AIM). Treatment with a folate-aminopterin conjugate (EC2319) targeting FR-{beta}-positive macrophages significantly reduced macrophage infiltration compared to saline (5.23 {+/-} 2.84% vs. 1.24 {+/-} 0.66%, P < 0.001) in rat experimental AIM. After immunization, FR-{beta} targeting positron emission tomography (PET) tracer [18F]FOL detected myocardial inflammatory lesions and revealed reduction in inflammation following EC2319 treatment relative to saline or tumor necrosis factor-alpha inhibitor Etanercept [standardized uptake value (SUV) 1.07 {+/-} 0.22 vs. 2.38 {+/-} 0.90 vs. 2.59 {+/-} 0.56, P < 0.001]. [18F]FOL PET signal correlated with myocardial CD68-positive macrophage content (r = 0.720, P < 0.001). These findings demonstrate that EC2319 attenuates myocardial inflammation in AIM and underscore the pathogenic role of FR-{beta}-positive macrophages. [18F]FOL PET provides a noninvasive means of detecting myocardial inflammatory activity and therapeutic response. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/686077v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@18e9296org.highwire.dtl.DTLVardef@139b8b3org.highwire.dtl.DTLVardef@8d1a74org.highwire.dtl.DTLVardef@1c3f06d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Functional interrogation uncovers a critical role for a high-plasticity cell state in lung adenocarcinoma

Plasticity--the ability of cells to undergo phenotypic transitions--drives cancer progression and therapy resistance1-3. To date, strategies targeting cancer plasticity have not advanced to the clinic due to a lack of fundamental understanding of the underlying mechanisms. Recent studies have suggested that plasticity in solid tumors is concentrated in a minority subset of cancer cells4-6, yet functional studies interrogating this high plasticity cell state (HPCS) in situ are lacking. Here, we developed mouse models enabling detection, longitudinal lineage tracing, and ablation of the HPCS in autochthonous lung tumors in vivo. Using lineage tracing, we uncover the HPCS cells are dedifferentiated but possess high capacity for cell state transitions, giving rise to both early neoplastic (differentiated) and advanced lung cancer cell states in situ. Longitudinal lineage tracing using secreted luciferases reveals HPCS-derived cells harbor high capacity for growth when compared to bulk cancer cells or another defined cancer cell state with features of differentiated lung epithelium. Suicide gene-mediated ablation of the HPCS in early neoplasias abrogates tumor progression. Ablating HPCS cells in established tumors by suicide gene or HPCS-directed CAR T cells robustly reduces tumor burden, whereas ablation of a differentiated lung cancer cell state had no effect. We further demonstrate that the HPCS gives rise to therapy-resistant cell states, whereas ablation of the HPCS abrogates resistance to chemotherapy and oncoprotein-targeted therapy. Interestingly, an HPCS-like state is ubiquitous in regenerating epithelia and in carcinomas of multiple other tissues, revealing a convergence of plasticity programs. Our work establishes the HPCS as a critical hub enabling reciprocal transitions between cancer cell states, including acquisition of states adapted to cancer therapies. Targeting the HPCS in lung cancer and in other carcinomas may suppress cancer progression and eradicate treatment resistance.

cancer biology↗

bioRxiv2025

Whole-transcriptome-scale and isoform-resolved spatial imaging of single cells in complex tissues

Cell and tissue functions arise from complex interactions among numerous genes, and a systematic understanding of these functions requires isoform-resolved, whole-transcriptome-scale analysis of single cells with high spatial resolution. Here, we introduce a spatial transcriptomics method based on a novel in situ RNA amplification strategy, enabling short RNA sequence detection and hence spatially resolved expression profiling of individual cells at the whole-transcriptome scale with splice-isoform resolution. Using this approach, we imaged [~]33,000 distinct RNAs--including [~]23,000 genes and [~]10,000 isoform-defining transcripts--in the mouse brain. Our data enabled systematic analyses of region- and cell-type-specific gene programs and ligand-receptor-based cell-cell communications. These data further revealed a rich spatial diversity and cell-type specificity in isoform usage across numerous genes and identified brain structures particularly enriched for specific isoform usage. We anticipate broad application of this method for molecular and cellular analysis of tissues, unlocking previously inaccessible discoveries in cell and organismal biology.

genomics↗

bioRxiv2025

L1CAM signaling through planar cell polarity generates SOX2+ metastatic progenitors in lung adenocarcinoma

Plasticity transitions during carcinoma progression generate fetal-like progenitor states with metastatic capacity. How these progenitors emerge and persist during tumor progression remains unknown. Here, we elucidate a process that drives the emergence of SOX2+ metastatic progenitors in lung adenocarcinomas (LUAD). LUAD cells in the tumor invasive front and distant metastases express the cell adhesion molecule L1CAM, a marker of regenerative epithelial progenitors and a mediator of cell-basement membrane and cell-cell interactions. L1CAM-mediated adhesion to perivascular basement membrane is known to stimulate the proliferation of extravasated micrometastatic cells. We now identify a distinct and broader role of L1CAM as promoter of the SOX2+ LUAD progenitor state. We show that L1CAM at cell-cell interfaces promotes the assembly of the planar cell polarity (PCP) complex in metastatic LUAD progenitors. L1CAM-dependent PCP acting through a non-canonical WNT signaling activates c-Jun, which cooperates with the chromatin remodeling factor CHD1 to drive SOX2 expression and metastatic activity. This axis sustains the tumor-initiating and regenerative capacity of LUAD progenitor cells. By illuminating the role of L1CAM and PCP signaling in the generation of SOX2+ LUAD progenitors, our findings identify potential new targets to treat metastatic cancer.

cancer biology↗