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Biology subjects

Gan, Y.

Publications and source records attributed to Gan, Y..

At least 19 recordsLinked to original sources

DNA-LLM2Vec: Architecture-Aware Task-Conditioned Adaptation of Decoder DNA Foundation Models

Decoder DNA foundation models pretrain with dense next-token prediction and scale to long sequences, but their representations are directional. This is a poor fit for genomic tasks that need sequence context both upstream and downstream of a locus. Bidirectional masked-language-model encoders supply this context, but they pretrain more sparsely and scale less easily to long windows. We introduce DNA-LLM2Vec, a staged decoder-to-encoder framework that opens bidirectional context, repairs the resulting mismatch with masked next-token prediction, and applies contrastive views encoding strand and positional invariance. We instantiate it on two architecturally distinct backbones, DNAGPT and HyenaDNA, and evaluate seven biological task families (grouped from GB, NT, GUE, and GUE+EPI) with frozen linear probing. The benefits of conversion are architecture-aware and task-conditioned rather than uniform. Crop-based positional contrastive learning helps most for the extended-context families (enhancer-promoter interaction and Virus-COVID), raising frozen Avg-EPI MCC to 27.5% for DNAGPT and 26.7% for HyenaDNA, whereas for shorter, local families the results depend on backbone and tokenisation. Beyond classification, bidirectional context and MNTP improve causal-eQTL variant-effect prediction specifically at distance, and a base-pair mutagenesis diagnostic shows that adaptation organises motif-aware contact structure while reverse-complement training imprints strand-consistent geometry, yet neither predicts the best downstream view. DNA-LLM2Vec therefore produces frozen bidirectional representations whose most effective adaptation view depends on the task structure and the backbone. Code and checkpoints are available at https://github.com/semi-nothing/dna-llm2vec.

bioinformatics↗

Distinct roles for partially redundant transcription factors in Caenorhabditis elegans mesoderm lineage development

Developmental transcription factors often have overlapping functions, making it difficult to define the distinct roles of individual factors during lineage specification. We investigated the partially redundant transcription factors TBX-35 and CEH-51 in the Caenorhabditis elegans embryonic MS mesodermal lineage using 4D lineage tracing, reporter imaging, genetics, and single-cell RNA sequencing. In tbx-35 mutants, MS descendants showed progressively slower cell cycles and a division pattern that increasingly resembled the cousin C lineage. Fate-regulator expression also shifted toward C-like features, including ectopic pal-1 and expanded HLH-1 expression, although mutant cells did not simply adopt normal C-lineage positions. Loss of tbx-35 also impaired a later MS-dependent Notch induction in the AB lineage while leaving an earlier induction intact. CEH-51 showed a different pattern of activity whereby its protein became enriched in anterior MS daughters, and ceh-51 mutants produced later, more restricted lineage defects that were strongest in descendants of cells with higher CEH-51 levels. Single-cell profiling identified overlapping but nonidentical sets of genes dependent on the two factors. TBX-35-dependent changes were strongest at earlier stages, whereas CEH-51-dependent genes became more prominent later and were enriched in anterior MS sublineages. Finally, temperature-shift experiments determined that the severity and onset of tbx-35 mutant phenotypes depend on the maternal temperature environment and cannot be explained by differences in residual CEH-51 expression. These findings reveal that TBX-35 and CEH-51 contribute differently across the MS lineage and that reliable mesoderm development is supported by overlapping zygotic and maternal regulatory inputs.

developmental biology↗

Identification of a neural circuit that enables safe, long-term torpor in mice

Torpor, a state of regulated hypothermia and hypometabolism, is a critical survival strategy in certain mammals. Previous studies established the primacy of neuron control in initiating acute torpor. However, whether neuromodulation can safely sustain torpor over the long term, and the specific governing pathways, remain unanswered challenges limiting its translational potential. Here we identify a distinct preoptic neuronal population expressing General control nonderepressible 2 ( G neurons) in mice that is essential and sufficient for torpor induction. Strikingly, sustained and selective activation of G neurons induces a stable, weeks-long torpid state (G neuron-driven long-term torpor, GLT), from which animals arouse without obvious behavioral deficits or tissue pathology. In contrast, long-term torpor driven by pan-neuronal activation of the same brain region (PLT) causes multiple post-recovery damages, underscoring the unique safety profile of selective pathway of G neurons. In a mouse cancer model, GLT directly suppressed tumor proliferation and markedly sensitized tumors to chemotherapy, achieving profound therapeutic outcomes. Together, we delineate a distinct neuronal population safely enabling prolonged torpor. This establishes a specific paradigm for inducing a stable and sustained hypometabolic state, providing a transformative platform for fundamental physiological research and pioneering clinical strategies against chronic pathologies such as cancer.

neuroscience↗

The tongue-brain axis mediates a hidden amino acid appetite

Selecting a diet containing all essential amino acids (EAAs) is critical for health. Following EAA deprivation, animals can select a nutritiously complete food source; however, the underlying mechanisms in vertebrates remain unclear. In mice, we show that leucine deficiency activates hypothalamic agouti-related protein (AgRP) neurons, which project to the paraventricular thalamus (PVT) via {gamma}-aminobutyric acid and are required for EAA deficiency-induced leucine appetite in mice. Furthermore, the peripheral tongue amino acid sensor general control nonderepressive-2 (GCN2) mediates acute EAA appetite via AgRP neurons. Together, these findings identify a tongue-AgRP-PVT circuit underlying EAA appetite, which is important for the rapid and accurate selection of essential nutrients.

neuroscience↗

Pharmacological recruitment of a VTA glutamatergic arousal circuit by the natural product BN3 drives broad-spectrum emergence from general anesthesia

Pharmacological control of emergence from general anesthesia remains strikingly limited. Clinically available antagonists are largely drug-class specific, leaving recovery dependent on anesthetic clearance rather than to an actively programmable switch in brain state. Through phenotypic screening of a structurally diverse natural-product library, we identified BN3 (L-(-)-camphor) as a broad-spectrum emergence agent. BN3 robustly shortened recovery from propofol anesthesia across species--from mice and rats to rabbits, dogs, and rhesus monkeys--and remained effective after continuous infusion. In rodents, BN3 also accelerated emergence from mechanistically distinct anesthetics, including etomidate, remimazolam, sodium {gamma} - hydroxybutyrate, midazolam, ketamine, sodium pentobarbital, and isoflurane. EEG recordings revealed a rapid cortical shift from slow-wave dominance to a wake-like high-frequency spectrum. Mechanistically, BN3 preferentially recruited ventral tegmental area (VTA) glutamatergic neurons: chemogenetic silencing abolished the BN3-evoked EEG spectral shift and strongly attenuated behavioral acceleration of emergence, whereas optogenetic activation of these neurons was sufficient to promote recovery. BN3 increased glutamate release in the nucleus accumbens and medial prefrontal cortex, and projection-specific inhibition of VTA[->]NAc or VTA[->]mPFC outputs blunted BN3-induced emergence. These findings define a VTA-centered glutamatergic arousal circuit that can be pharmacologically recruited as a common gateway for anesthetic-independent emergence.

neuroscience↗

TRPV4 Inhibition by a Natural Product Mediates Analgesia

The transient receptor potential vanilloid 4 (TRPV4) channel, a polymodal calcium-permeable cation channel, is activated by diverse stimuli, including hyposmolarity, moderate heat, mechanical stress, and acidic pH. TRPV4 plays a critical role in the onset and progression of pain and is implicated in multiple pathological conditions, positioning it as an attractive therapeutic target. However, the development of TRPV4-targeted therapeutics has been hindered by limited mechanistic understanding of its inhibition. Here, the natural product (R)-1-(3-ethylphenyl)ethane-1,2-diol (AH001) is identified as a potent, subtype-selective TRPV4 inhibitor. A potential gating mechanism of TRPV4 inhibition is proposed through a combination of structural analyses and site-directed mutagenesis. Electrophysiological studies and cryo-electron microscopy (cryo-EM) further reveal that AH001s glucuronide metabolite, AHP, retains robust TRPV4 inhibitory activity, providing a critical structural basis for rational optimization of AH001 as a lead compound. Notably, AH001 demonstrated significant efficacy in reducing neuronal hyperexcitability in dorsal root ganglia (DRGs) and produced pronounced analgesic effects across multiple pain models, highlighting its therapeutic potential in pain relief. This study offers critical structural and mechanistic insights into TRPV4 inhibition and lays the groundwork for the structure-based design of TRPV4-targeted therapeutics.

biochemistry↗

scHG: a supercell framework with high-order graph learning enables hyper-fast multi-omics analysis

Multi-omics profiling--spanning proteomics, transcriptomics, and additional omics data types--is rapidly advancing, providing increasingly detailed maps of cellular identity and function. In parallel, computational methods have evolved to integrate diverse omics with increasing precision in resolving cellular heterogeneity and delineating subtle subpopulation structures. Yet, capturing rare cell population while maintaining computational tractability remains a major challenge. Here, we introduce the supercell paradigm, in which expression-coherent cells are compressed into candidate units for rare cell population. Supercells are constructed using angle-aware similarity metrics and second-order co-occurrence neighbors, with impurity cells pruned by degree centrality. To address scalability, we implement sparse matrix optimization and iterative high-order graph updates, enabling efficient integration of large-scale multi-omics datasets. Building on this framework, we develop scHG, a high-order graph learning approach guided by an omics-weighted optimizer that adaptively balances contributions from gene expression, surface proteins, and chromatin accessibility. Across six benchmark datasets (up to 30672 cells), scHG consistently outperforms state-of-the-art methods, improving mean ARI and NMI by 3.97% and 3.54%, respectively, while reducing runtime by 26.40%. Beyond performance gains, scHG was able to resolve fine-grained cellular heterogeneity within conventionally defined T cell populations, distinguishing subpopulations such as memory-like or progenitor-exhausted T cells and innate-like cytotoxic T cells. At the same time, the supercell framework uncovered rare populations, including dendritic-cell populations and NK-like B cells, that remained masked at the cluster level under standard pipelines. These results underscore both the rare-cell detection capability and the computational efficiency of scHG. Our code and data are available at http://mialab.ruc.edu.cn/scHG_code/zip.

bioinformatics↗

Global Insights into Evolution and Adaptation in KPC and NDM Coproducing Carbapenem-Resistant Klebsiella pneumoniae.

ObjectivesThe worldwide dissemination of carbapenem-resistant Klebsiella pneumoniae co-producing KPC and NDM (KPC-NDM-CRKP) poses a substantial clinical challenge. MethodsThis study characterized 5 KPC-NDM-CRKP isolates from a tertiary hospital in southern China and integrated 460 global isolates genomes to demonstrate the population framework of this epidemic pathogen. Results5 clinical isolates were multidrug resistance, exhibiting high level resistance to first-line drugs including carbapenems and ceftazidime/avibactam. Globally, KPC-2-NDM-1 (50.3%) were the most common and an increasing trend of ST11-KL64 (20%) isolates carrying iucA and rmpA/A2. Resistance and virulence genes were positively associated with specific mobile elements including blaKPC-3 with Tn4401, iucABC with IncHI1B, iroBCDN with IncQ1. The phylogenetic analysis revealed distinct lineage-specific mutations and pan-genome enrichments synergistically promoted adaptive evolution: cluster 1 had membrane transport and secretion but enhanced immune evasion and horizontal gene transfer, cluster 3 adapted metabolically for nutrient-limited niches; cluster 4 reprogrammed metabolism for host adaptation, cluster 6 displayed membrane repair and reduced virulence (e.g., KC187). High-risk iucA/rmpA-positive isolates in cluster 2 acquired enhanced virulence and metabolic adaptive capacity through recombination hotspots (ABC transporters DdpABCD, efflux systems MdtABCD, metabolic enzymes XylB and MtlD, regulators BaeR and OmpR) and pan-genome enrichment (siderophore biosynthesis, toxin-antitoxin VapC and restriction-modification systems). Functionally, these traits correlated with high mucoviscosity, serum resistance, siderophore production and lower survival rates in G. mellonella that contribute to epidemiological success. ConclusionsThese findings demonstrated the discrete mutation, horizontal transfer, and accessory genome plasticity collectively drove the epidemiological success of KPC-NDM-CRKP.

microbiology↗

Biodegradation of the endocrine-disrupting compound bisphenol F by Sphingobium yanoikuyae DN12

Bisphenol F (BPF) is an emerging environmental pollutant widely present in surface water and wastewater systems. Microbial activity is crucial in driving its degradation, offering a potential avenue for mitigating its environmental impact. Although the degradation pathway for BPF has been identified in various bacteria, the biodegradation mechanisms remain unclear. In this study, we isolated a highly efficient BPF-degrading strain of Sphingobium yanoikuyae DN12, which could utilize BPF as the sole carbon source and energy source for growth, from a river sediment in Anhui Province China. Through Ultra performance liquid chromatography high-resolution mass spectrometry (UPLC-HRMS) analysis, we found that oxidation and hydrolysis are key steps for BPF biodegradation. Utilizing whole-genome sequencing, comparative transcriptomics analysis and biochemical identification, a gene cluster bpf was identified to be involved in BPF degradation. BpfAB is a two-component oxidoreductase responsible for converting BPF to 4,4-dihydroxybenzophenone (DHBP). BpfC is a Baeyer-Villiger monooxygenase (BVMO) responsible for converting DHBP to 4-hydroxyphenyl-4-hydroxybenzoate (HPHB). Isotope tracing demonstrated that the oxygen atom incorporated by BpfAB originates from water, whereas that incorporated by BpfC derives from molecular oxygen (O2). BpfD is an /{beta} hydrolase responsible for converting HPHB to 4-hydroxybenzoate (4HB) and 1,4-hydroquinone (HQ). Analysis of the taxonomic and habitat of 325 prokaryotic genomes revealed that BpfA-like homologs are predominantly found in the phylum Pseudomonadota, primarily inhabiting soil and aquatic environments. This study enhances our understanding of the biodegradation mechanism of BPF, and provides guidance for the effective remediation of BPF-contaminated environments. IMPORTANCEBPF is a widely used alternative to bisphenol A and poses a growing threat to ecosystems and human health due to its environmental persistence and endocrine-disrupting effects. Although microbial degradation pathways for BPF have been reported, the key enzymes involved and their catalytic mechanisms remain unclear. This work reports the isolation of a Sphingobium strain capable of mineralizing BPF and the genetic basis for the catabolic pathway. Three enzymes--a two-component oxidoreductase, a Baeyer-Villiger monooxygenase, and an /{beta} hydrolase--were biochemically characterized and shown to catalyze the three critical steps in BPF degradation. These findings provide insights into the biochemical processes involved in the microbial degradation of BPF.

microbiology↗

A personalized multi-platform assessment of somatic mosaicism in the human frontal cortex

Somatic mutations in individual cells create genomic mosaicism, influencing genetic disorders and cancers. While clonal mutations in cancers are well-studied, rarer somatic variants in normal tissues remain poorly characterized. This study systematically evaluates detection methods using a personalized donor-specific assembly (DSA) from a neurotypical individuals dorsolateral prefrontal cortex assessed with Oxford Nanopore, NovaSeq, linked-read sequencing, Cas9-targeted long-read sequencing (TEnCATS), and single-neuron MALBAC amplification. The haplotype-resolved DSA improved cross-platform analysis, dramatically increasing phasing rates. Germline SNVs, structural variations (SVs), and transposable elements (TEs) were recalled with 99.4%-99.7% accuracy in bulk tissue, and phased haplotype analysis reduced false positives by 15.4%-75.1% for putative somatic candidates. Long-read single-neuron sequencing detected nine somatic SV candidates, demonstrating enhanced sensitivity for rare variants, while TEnCATS identified eight low-frequency somatic TE candidates. These findings highlight advanced methodologies for precise somatic variant detection, critical for understanding mosaicisms role in health and disease.

genomics↗

A comprehensive analysis of the potential biological functions and prognostic values of SREBF1 for multiple cancer types including colorectal cancer

As an important molecule involved in lipid metabolism, Sterol Regulatory Element-Binding Protein 1 (SREBF1) plays a critical role in governing cellular lipid synthesis and uptake. However, a comprehensive understanding of the biological significance of SREBF1 in pan-cancer remains elusive. In this study, we aimed to comprehensively analyze the functional characteristics of SREBF1 in human cancers, including colorectal cancer (CRC). Our study utilized various databases and tools such as TCGA, GEO, TIMER2.0, GEPIA2.0, UALCAN, and the Human Protein Atlas to examine SREBF1 expression, genetic alterations, immune infiltration, single-cell sequencing, survival analysis, and gene enrichment. The results revealed that the expression of SREBF1 exhibited significant variations across different cancer types, and was closely associated with patient prognosis and immune infiltration. Moreover, the gene function assays indicated SREBF1 significantly affect cell growth and migration. Overall, the findings suggest that SREBF1 could serve as a potential prognostic biomarker and a novel therapeutic target in different cancer types.

cancer biology↗

Deep learning based genomic breeding of pest-resistant grapevine

Crop pests have profoundly deleterious effects on crop yield and food security. However, conventional pest control depends heavily on the utilization of insecticides, which develops strong pesticide resistance and concerns of food safety. Crop and their wild relatives display diverse levels of pest resistance, indicating the feasibility for breeding of pest-resistant crop varieties. In this study, we integrate deep learning (DL)/machine learning (ML) algorithms, plant phenomics and whole genome sequencing (WGS) data to conduct genomic selection (GS) of pest-resistance in grapevine. We employ deep convolutional neural networks (DCNN) to accurately calculate the severity of damage by pests on grape leaves, which achieves a classification accuracy of 95.3% (Visual Geometry Group 16, VGG16, for binary trait) and a correlation coefficient of 0.94 in regression analysis (DCNN with Pest Damage Score, DCNN-PDS, for continuous trait). We apply DL models to predict and integrate phenotype (both binary and continuous) along with WGS data from 231 grape accessions, conducting Genome-Wide Association Studies (GWAS). This analysis detects a total of 69 QTLs, encompassing 139 candidate genes involved in pathways associated with pest resistance, including jasmonic acid (JA), salicylic acid (SA), ethylene, and other related pathways. Furthermore, through the combination with transcriptome data, we identify specific pest-resistant genes, such as ACA12 and CRK3, which play distinct roles in resisting herbivore attacks. Machine learning-based GS demonstrates a high accuracy (95.7%) and a strong correlation (0.90) in predicting the leaf area damaged by pests as binary and continuous traits in grapevine, respectively. In general, our study highlights the power of DL/ML in plant phenomics and GS, facilitating genomic breeding of pest-resistant grapevine.

plant biology↗

Integrative genomics reveals the polygenic basis of seedlessness in grapevine

Seedlessness is a crucial quality trait in table grape (Vitis vinifera L.) breeding. However, the development of seeds involved intricate regulations, while the polygenic basis of seed abortion remains unclear. Here, we combine comparative genomics, population genetics, quantitative genetics, and integrative genomics to unravel the evolution and polygenic basis of seedlessness in grapes. We generated four haplotype-resolved telomere-to-telomere (T2T) genomes for two seedless grape cultivars, Thompson Seedless (TS, syn. Sultania) and Black Monukka (BM). Comparative genomics identified a [~]4.25 Mb hemizygous inversion on Chr10 specific in seedless cultivars, with seedless-associated genes VvTT16 and VvSUS2 located at breakpoints. Population genomic analyses of 548 grapevine accessions revealed two distinct clusters of seedless cultivars, tracing the origin of the seedlessness trait back to Sultania. Introgression, rather than convergent selection, shaped the evolutionary history of seedlessness in grape improvement. Genome-wide association study (GWAS) analysis identified 110 quantitative trait loci (QTLs) associated with 634 candidate genes, including novel candidate genes, such as three 11S GLOBULIN SEED STORAGE PROTEIN and two CYTOCHROME P450 genes, and well-known genes like VviAGL11. Integrative genomic analyses resulted in 339 core candidate genes categorized into 13 groups related to seed development. Machine learning based genomic selection achieved a remarkable 99% precision in predicting grapevine seedlessness. Our findings highlight the polygenic nature of seedless and provide novel candidate genes for molecular genetics and an effective prediction for seedlessness in grape genomic breeding.

genetics↗

Bi-parental graph strategy to represent and analyze hybrid plant genomes

Hybrid plants are universally existed in wild and often exhibit greater performance of complex traits compared with their parents and other selfing plants. This phenomenon, known as heterosis, has been extensively applied in plant breeding for decades. However, the process of decoding hybrid plant genomes has seriously lagged due to the challenges in their genome assembling and the lack of proper methods to further represent and analyze them. Here we report the assembly and analysis of two hybrids: an intraspecific hybrid between two maize inbred lines and an interspecific hybrid between maize and its wild relative teosinte, based on the combination of PacBio High Fidelity (HiFi) sequencing and chromatin conformation capture sequencing data. The haplotypic assemblies are well-phased at chromosomal scale, successfully resolving the complex loci with extensive parental structural variations (SVs). By integrating into a bi-parental genome graph, the haplotypic assemblies can facilitate downstream short-reads based SV calling and allele-specific gene expression analysis, demonstrating outstanding advantages over one single linear genome. Our work provides an entire workflow which hopefully can promote the deciphering of the large numbers of hybrid plant genomes, especially those whose parents are unknown or unavailable and help to understand genome evolution and heterosis.

bioinformatics↗

Discovery of fibrotic intervertebral disc in mice

Intervertebral discs are crucial to spine flexibility and stability during locomotion, but the mechanism of their mechanoadaptation to stress remains inadequately elucidated. We discovered spontaneous collagenesis in discs at the tail base in mice occurring from 14 days post-natal development. These discs termed as type C, differ from typical discs by exhibiting intensive collagen II and reduced aggrecan deposition contributing to the stiffening of the extracellular matrix (ECM), without typical degenerative markers. The reinforced mechanical properties enable type C discs to withstand high mechanical stress during flexion. Further analysis revealed that type C discs experience a turnover in cell composition, with the emergence of Procr+ progenitor cells and depletion of notochord cells. We demonstrated the essential role of mechanical stress in type C disc formation, suggesting a mechanoadaptive process rather than a pathological condition. Mechanistically, we identified TRPV4, as pivotal factors in collagen II synthesis in type C discs, highlighting the role of mechanotransduction in this adaptation. Our findings introduce a novel mechanoadaptive process of intervertebral disc by orchestrating collagenesis, advancing understanding of diverse disc functions in spine development and homeostasis, thereby providing insights for leveraging this mechanism to address spinal disorders.

pathology↗

Image Analysis Techniques for In Vivo Quantification of Cerebrospinal Fluid Flow

Over the last decade, there has been a tremendously increased interest in understanding the neuro-physiology of cerebrospinal fluid (CSF) flow, which plays a crucial role in clearing metabolic waste from the brain. This growing interest was largely initiated by two significant discoveries: the glymphatic system (a pathway for solute exchange between interstitial fluid deep within the brain and the CSF surrounding the brain) and meningeal lymphatic vessels (lymphatic vessels in the layer of tissue surrounding the brain that drain CSF). These two CSF systems work in unison, and their disruption has been implicated in several neurological disorders including Alzheimers disease, stoke, and traumatic brain injury. Here, we present experimental techniques for in vivo quantification of CSF flow via direct imaging of fluorescent microspheres injected into the CSF. We discuss detailed image processing methods, including registration and masking of stagnant particles, to improve the quality of measurements. We provide guidance for quantifying CSF flow through particle tracking and offer tips for optimizing the process. Additionally, we describe techniques for measuring changes in arterial diameter, which is an hypothesized CSF pumping mechanism. Finally, we outline how these same techniques can be applied to cervical lymphatic vessels, which collect fluid downstream from meningeal lymphatic vessels. We anticipate that these fluid mechanical techniques will prove valuable for future quantitative studies aimed at understanding mechanisms of CSF transport and disruption, as well as for other complex biophysical systems.

neuroscience↗

Bioorthogonal in-cell Labeling and Profiling of N6-isopentenyladenosine (i6A) Modified RNA

Chemical modifications in RNAs play critical roles in structural diversification and functional regulation of many vital biochemical processes. Several hydrophobic prenyl-modifications have been discovered in a variety of RNA species since the 1990s. Prenyl groups are the feedstocks of terpene and many other biological molecules and the processes of prenylation in different macromolecules have been widely studied. We present here a new chemical biology technique to identify and label i6A, a prenyl-modified RNA residue, based on the unique reactivity of the prenyl group. We also found that iodine-mediated cycloaddition reactions of the prenyl group occurs in a superfast manner, and converts i6A from a hydrogen-bond acceptor into a donor. Based on this reactivity, we developed an iodine-mediated oxidation and reverse transcription (IMORT) method to profile cellular i6A residues with a single-base resolution, allowing for the transcriptome-wide detection and analysis of various i6A-containing RNA species.

biochemistry↗

WNT5A-RHOA axis is a new vulnerability in small-cell lung cancer

WNT signaling presents an attractive target for cancer therapy due to its widespread oncogenic role. However, the molecular players involved in WNT signaling and the impact of their perturbation remain unknown for numerous recalcitrant cancers including small-cell lung cancer (SCLC). Here we show that beta-catenin, a master mediator of canonical WNT signaling, is not required for SCLC development in genetically engineered mouse models (GEMMs) and its transcriptional program is largely silenced during tumor development. Instead, inactivation of p130 in SCLC cells induces expression of WNT5A, a ligand for beta-catenin-independent WNT pathways. WNT5A is both sufficient and required for SCLC development and cell proliferation and selectively induces Rhoa transcription and activates RHOA protein to drive SCLC. Rhoa knockout suppresses SCLC development in vivo, and chemical perturbation of RHOA selectively inhibits SCLC cell proliferation. These findings suggest a novel requirement for the WNT5A-RHOA axis in SCLC that is distinct from other noncanonical WNT pathways. This vulnerability of p130-WNT5A-RHOA pathway provides critical insight into the development of novel therapeutic strategies for the recalcitrant cancer, as well as the stratification of patients who may benefit from them. This study also sheds new light on the heterogeneity of WNT signaling and the molecular determinants of its cell-type specificity.

cancer biology↗