Biology subjects

Huang, Y.

Publications and source records attributed to Huang, Y..

At least 577 records · Page 32Linked to original sources

bioRxiv2023

An uncanonical CDK6 activity inhibits cilia function by suppressing axoneme polyglutamylation

Tubulin polyglutamylation is a post-translational modification that occurs primarily along the axoneme of cilia. Defective axoneme polyglutamylation impairs cilia function and has been correlated with ciliopathies, including Joubert Syndrome (JBTS). However, the precise mechanisms regulating proper axoneme polyglutamylation remain vague. Here, we show that Cyclin-Dependent Kinase 6 (CDK6), but not its paralog CDK4, localizes to cilia base and suppresses axoneme polyglutamylation by phosphorylating RAB11-interacting protein FIP5 at site S641, a critical regulator of cilia import of glutamylases. S641 phosphorylation disrupts the ciliary recruitment of FIP5 by impairing its association with RAB11, thereby reducing the ciliary import of glutamylases. Interestingly, significant upregulation of CDK6 and defective axoneme polyglutamylation were observed in Autosomal dominant polycystic kidney disease (ADPKD) cells. Encouragingly, the FDA-approved CDK4/6 inhibitor Abemaciclib can effectively restore cilia function in JBTS and ADPKD cells with defective glutamylation and suppresses renal cystogenesis in an ex vivo ADPKD model. In summary, our study elucidates regulatory mechanisms governing axoneme polyglutamylation and suggests developing CDK6-specific inhibitors could be a promising therapeutic strategy to enhance cilia function in ciliopathy patients.

cell biology↗

bioRxiv2023

Tumor-derived exosomal miR-222-3p induce cancer-associated fibroblasts activation to foster progression of renal cancer

The interaction between tumor-derived exosomes and stroma is crucial for tumor progression. However, the mechanisms by which tumor cells influence stromal changes are not yet fully understood. Our study revealed that high-metastatic renal cancer cells are more effective in converting normal fibroblasts into cancer-associated fibroblasts (CAFs) compared to low-metastatic renal cancer cells. Meanwhile, high-metastatic renal cancer cells secrete more exosomal miR-222-3p, which can directly target PANK3, activate NF-kB signaling pathway in fibroblasts and induce intracellular metabolic reprogramming to produce more lactic acid through Warburg effect. The activated CAFs further promote renal cancer progression by secreting lactic acid and inflammatory cytokines, including IL-6 and IL-8. Patients with renal cancer who have high levels of serum exocrine miR-222-3p are more likely to experience progression. These findings suggest that the intercellular communication between renal cancer cells and fibroblasts is facilitated by tumor exosomes. Targeting this communication may hold promise for the prevention and treatment of renal cancer.

cancer biology↗

bioRxiv2023

Multi-omics analysis of Bacillus. subtilis spores formed at different environmental temperatures reveal differences at the morphological and molecular level.

Spore-forming bacteria play an essential role in the food industry and public health. Through sporulation, bacteria can withstand extreme environmental conditions that vegetative cells cannot survive. Although it is well established that the same environmental factors that affect the growth of vegetative cells also profoundly influence sporulation, the mechanisms of how growth conditions affect spore structure and function remain unknown. Prior research has shown that spores prepared at higher temperatures are more heat resistant than those prepared at lower temperatures. The present study examines, both at metabolomic and proteomic levels, the effect of different sporulation temperatures (25, 37 and 42{degrees}C) on the small molecule and protein composition of spores (strain PY79) of the model organism B. subtilis. Through differential harvesting times, spores of the same developmental stage were obtained for each temperature regime. The heat resistance, dipicolinic acid content, germination kinetics and spore morphology were assayed to compare spore properties. Metabolome and proteome analysis yielded unparalleled broad molecular detail of the spores formed at different environmental temperatures. Our findings indicate that peptidoglycan biosynthesis and 28 outer-layer proteins play a crucial role in the functional diversity of spores produced by B. subtilis under varying temperatures.

microbiology↗

bioRxiv2023

Distinguished biological adaptation architecture aggravated population differentiation of Tibeto-Burman-speaking people inferred from 500 whole genome data from 39 populations

Tibeto-Burman (TB) people have tried to adapt to the hypoxic, cold and high-UV high-altitude Tibetan Plateau and complex disease exposure in the lowland wet and hot rainforest since the late Paleolithic period. However, the full landscape of genetic history and biological adaptation of geographically diverse TB people and their interaction mechanism remained unknown. We generated a whole-genome-based meta-database of 500 individuals from 39 TB populations from East Asia and Southeast Asia and presented a comprehensive landscape of genetic diversity, admixture history and differentiated adaptative features of geographically different TB people. We identified geography/language-related genetic differentiation among Tibetan Plateau, Tibetan-Yi-Corridor (TYC) and Southeast Asian TB people, consistent with their differentiated admixture process with incoming or indigenous ancestral source populations. A robust genetic connection between TYC people and ancient YR people supported the Northern origin hypothesis of TB people. We reported population substructure-related differentiated biological adaptative signatures between highland Tibetans and lowland TB people and between geographically different Lolo speakers. Highland adaptative EPAS1 and EGLN variants riched in Tibetans but lacked in TYC people whose adaptation is associated with the physical features and skin pigmentation (EDAR and SLC24A5), hepatic alcohol metabolism (ALDH9A1), regulation of cell-cell adhesion of muscle cells (CTNNA3) and immune/fat metabolism-related adaptative signature. TB-related genomic resources provided new insights into the genetic basis of phenotype differences and better reference for the anthropologically-informed sampling design in biomedical and genomic cohort research.

genetics↗

bioRxiv2023

Integrative metabolomics and proteomics allow the global intracellular characterization of Bacillus subtilis cells and spores.

Reliable and comprehensive multi-omics analysis is essential for researchers to understand and explore complex biological systems more completely. Bacillus subtilis is a model organism for Gram-positive spore-forming bacteria, and in-depth insight into the physiology and molecular basis of spore formation and germination in this organism requires advanced multilayer molecular datasets generated from the same sample. In this study, we evaluated two monophasic methods for polar and nonpolar compound extraction (acetonitrile/methanol/water; isopropanol/water, and 60% ethanol), and two biphasic methods (chloroform/methanol/water, and methyl tert-butyl ether/methanol/water) on coefficients of variation of analytes, identified metabolite composition and the quality of proteomics profiles. The analytical workflow comprises (1) parallel metabolite and protein extraction, (2) monophasic or biphasic sample extraction, (3) proteomics comparison and (4) multi-omics-based data visualization. The 60% EtOH protocol proved to be the easiest in sample processing and more amenable to automation. Collectively, we annotated 505 and 484 metabolites and identified 1665 and 1562 proteins in B. subtilis vegetative cells and spores, respectively. We also show differences between vegetative cells and spores from a multi-omics perspective and demonstrated that an integrative multi-omics analysis can be implemented from one sample using the 60% EtOH protocol. Correlation analysis further demonstrated that the metabolome and proteome datasets were highly correlated in content for components annotated to be part of the pyrimidine metabolism pathway. The results obtained by the 60% EtOH protocol provide a comprehensive insight into differences in the metabolic and protein makeup of B. subtilis vegetative cells and spores. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/545067v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@18b0206org.highwire.dtl.DTLVardef@1321433org.highwire.dtl.DTLVardef@cc5e6eorg.highwire.dtl.DTLVardef@14bac12_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Humanized yeast to study the role of human ECE-1 isoforms in apoptosis in congenital heart diseases

Endothelin convert enzyme-1(ECE-1) plays a significant role in cardiovascular development including four isoforms with unclear function. Therefore, we are interested in studying the function of ECE-1 isoforms through mitochondria due to the high correlation between congenital heart disease (CHD) and apoptosis. Since the expression of human Bax and Bcl-xL in budding yeast (Saccharomyces cerevisiae) results in similar effects in mammalian cells, a yeast system was generated for mimicking human Bax-induced apoptosis and the expression of human ECE-1 isoforms was involved. The correlation between Bax-induced growth defect and the candidates of apoptosis via mitochondrial pathway was preliminarily investigated in this system. Furthermore, the phenotypes of ECE-1 isoforms have been identified through yeast growth defect. Individual ECE-1 isoform does not affect yeast growth but act as enhancers for the Bax-induced growth defect. ECE-1c is the strongest enhancer that affect the expression of candidates of outer membrane translocases. This study indicates that ECE-1 might play an important role in inducing apoptosis and we speculate these findings are possible to provide new perspectives with clarifying the mechanism of CHD.

molecular biology↗

bioRxiv2023

Comprehensive Characterization and Global Transcriptome Analyses of Human Fetal Liver Terminal Erythropoiesis

The fetal liver (FL) is the key erythropoietic organ during fetal development, but knowledge on human FL erythropoiesis is very limited. In this study, we sorted primary erythroblasts from FL cells and performed RNA sequencing analyses. We found that temporal gene expression patterns reflected changes in function during primary human FL terminal erythropoiesis. Notably, expression of genes enriched in proteolysis and autophagy was upregulated in orthochromatic erythroblasts (OrthoE), suggesting involvement of these pathways in enucleation. We also performed RNA sequencing of in vitro cultured erythroblasts derived from FL CD34+ cells. Comparison of transcriptomes between the primary and cultured erythroblasts revealed significant differences, indicating impacts of the culture system on gene expression. Notably, lipid metabolism gene expression was increased in cultured erythroblasts. We further immortalized erythroid cell lines from FL and cord blood (CB) CD34+ cells (FL-iEry and CB-iEry, respectively). FL-iEry and CB-iEry are immortalized at the proerythroblast stage and can be induced to differentiate into OrthoE, but their enucleation ability is very low. Comparison of transcriptomes between OrthoE with and without enucleation capability revealed downregulation of pathways involved in chromatin organization and mitophagy in OrthoE without enucleation capacity, indicating that defects in chromatin organization and mitophagy contribute to the inability of OrthoE to enucleate. Additionally, the expression levels of HBE1, HBZ, and HBG2 were upregulated in FL-iEry compared with CB-iEry, and this was accompanied by downregulation of BCL11A and upregulation of LIN28B and IGF2BP1. Our study provides new insights into human FL erythropoiesis and rich resources for future studies.

cell biology↗

bioRxiv2023

CHPF boosts proliferation and invasion of clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (ccRCC) is a malignant tumor most commonly seen in the urinary system, featuring quick progression, invasive behavior, frequent recrudesce, and bad prognosis, whereas Chondroitin polymerizing factor (CHPF) is an essential glycosyl transferase of biosynthesis involved chondroitin sulphate. But the relationship between the two has not been fully understood so far. The present research will probe into the relationship between CHPF and ccRCC. MethodsExplore the CHPF expression level in renal ccRCC tissues through bioinformatics analysis of The Cancer Genome Atlas (TCGA) and the real-time quantitative polymerase chain reaction detection system (qPCR); acquire relevant clinical data from the TCGA data-base and use Kaplan-Meier survival analysis to verify the relevance of CHPF expression to the clinical prognosis of ccRCC patients; then, effectively silence CHPF in ccRCC 786-O cells by a lentivirus-mediated approach; next, observe the effects of CHPF on tumor cell proliferation, cell cycle progression, and apoptosis. ResultsIn ccRCC tissues, CHPF expression has been significantly upregulated; the higher expression, the shorter survival of ccRCC patients. CHPF downregulation in the 786-O cell can effectively hold back the proliferation, apoptosis and cycle of cancer cells. ConclusionBased on the above results, we arrive at a conclusion that CHPF expression contributes markedly to the development of human ccRCC cells. Therefore, CHPF may act as a potential prognostic marker of ccRCC and provide a new target for ccRCC treatment. Simple SummaryChondroitin polymerizing factor (CHPF) is an important glycosyltransferase involved in the biosynthesis of chondroitin sulfate, which is thought to have some pro-carcinogenic effects. However, the role and mechanism of CHPF in clear cell renal cell carcinoma (ccRCC) have not been reported. The aim of this study was to investigate the relationship between CHPF and ccRCC. In this study, we found that CHPF was highly expressed in ccRCC and knocking out CHPF can greatly inhibit the proliferation and cell cycle progression of ccRCC and accelerate its apoptosis, suggesting that CHPF can predict the prognosis of ccRCC and a potential target for treatment.

genetics↗

bioRxiv2023

METTL16 Controls Kaposi's Sarcoma-Associated Herpesvirus Replication by Regulating S-Adenosylmethionine Cycle

Oncogenic Kaposis sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases, both of which are important for the development of KSHV- related cancers. As one of the most abundant RNA modifications, N6-methyladenosine (m6A) and its related complexes regulate KSHV life cycle. However, the role of METTL16, a new RNA methyltransferase, in KSHV life cycle remains unknown. In this study, we have identified a suppressive role of METTL16 in KSHV lytic replication. METTL16 knockdown increased while METTL16 overexpression reduced KSHV lytic replication. METTL16 binding to and writing of m6A on MAT2A transcript are essential for its splicing, maturation and expression. As a rate-limiting enzyme in the methionine- S-adenosylmethionine (SAM) cycle, MAT2A catalyzes the conversion of L-methionine to SAM required for the transmethylation of protein, DNA and RNA, transamination of polyamines, and transsulfuration of cystathionine. Consequently, knockdown or chemical inhibition of MAT2A reduced intracellular SAM level and enhanced KSHV lytic replication. In contrast, SAM treatment was sufficient to inhibit KSHV lytic replication and reverse the effect of the enhanced KSHV lytic program caused by METTL16 or MAT2A knockdown. Mechanistically, METTL16 or MAT2A knockdown increased while SAM treatment decreased the intracellular reactive oxygen species level by altering glutathione level, which is essential for efficient KSHV lytic replication. These findings demonstrate that METTL16 suppresses KSHV lytic replication by modulating the SAM cycle to maintain intracellular SAM level and redox homeostasis, thus illustrating the linkage of KSHV life cycle with specific m6A modifications, and cellular metabolic and oxidative conditions.

microbiology↗

bioRxiv2023

Dynamic phytomeric growth contributes to local adaptation in barley

Vascular plants segment their body axis with iterative nodes of lateral branches and internodes. Appropriate node initiation and internode elongation are fundamental to plant fitness and crop yield formation; but how they are spatiotemporally coordinated remains elusive. We show that in barley (Hordeum vulgare L.), selections under domestication have extended the apical meristematic phase to promote node initiation, but constrained subsequent internode elongation. In both vegetative and reproductive axes, internode elongation displays a dynamic proximal - distal gradient, and among subpopulations of domesticated barleys at the global range, node initiation and proximal internode elongation are associated with latitudinal and longitudinal gradients, respectively. Genetic and functional analysis suggest that, in addition to their converging roles in node initiation, flowering time genes are repurposed to specify the dynamic internode elongation. Our study provides an integrated view of barley node initiation and internode elongation, and suggests that plant architecture has to be recognized as dynamic phytomeric units in the context of crop evolution.

plant biology↗

bioRxiv2023

Engineering ligand stabilized aquaporin reporters for magnetic resonance imaging

Imaging transgene expression in live tissues requires reporters that are detectable with deeply penetrant modalities, such as magnetic resonance imaging (MRI). Here, we show that LSAqp1, a water channel engineered from aquaporin-1, can be used to create background-free, drug-gated, and multiplex images of gene expression using MRI. LSAqp1 is a fusion protein composed of aquaporin-1 and a degradation tag that is sensitive to a cell-permeable ligand, which allows for dynamic small molecule modulation of MRI signals. LSAqp1 improves specificity for imaging gene expression by allowing reporter signals to be conditionally activated and distinguished from the tissue background by difference imaging. In addition, by engineering destabilized aquaporin-1 variants with different ligand requirements, it is possible to image distinct cell types simultaneously. Finally, we expressed LSAqp1 in a tumor model and showed successful in vivo imaging of gene expression without background activity. LSAqp1 provides a conceptually unique approach to accurately measure gene expression in living organisms by combining the physics of water diffusion and biotechnology tools to control protein stability.

bioengineering↗

bioRxiv2023

Dissection of anterior mesendoderm segregation at single cell level in zebrafish

During gastrulation, the mesendoderm is firstly specified by morphogens such as Nodal, and then segregates into endoderm and mesoderm in a Nodal concentration-dependent manner. However, the mechanism underlying the segregation and crosstalk of different sub-groups within the meso- and endoderm lineages remains unclear. Here, taking zebrafish prechordal plate (PP) and anterior endoderm (Endo) as research model, using single-cell multi-omics and live imaging analyses, we show that anterior Endo progenitors originate directly from PP progenitors. A single-cell transcriptomic trajectory analysis of wild-type, ndr1 knockdown and lft1 knockout Nodal explants confirms the diversification of anterior Endo fate from PP progenitors. Gene Ontology (GO) enrichment analysis identifies that the change of chromatin organization potentiates the segregation of anterior endodermal cell fate from PP progenitors. Single-cell ATAC & RNA sequencing further reveals that two transcriptional regulators, gsc and ripply1, exhibit varied activation patterns in PP and anterior Endo cell trajectories at both the chromatin and RNA expression levels. We further demonstrate that Ripply1 functions coordinately with Gsc to repress anterior endodermal cell fate by directly binding to the cis-elements of sox32. Modulating the expression levels of these regulators tilts the cell fate decision between the PP and anterior Endo.

developmental biology↗

bioRxiv2023

TREM2 promotes glioma progression and angiogenesis mediated by microglia/brain macrophages

TREM2, a myeloid cell-specific signaling molecule, controls essential functions of microglia and impacts on the pathogenesis of Alzheimers disease and other neurodegenerative disorders. TREM2 is also highly expressed in tumor-associated macrophages and plays detrimental roles in an experimental mouse sarcoma model. Here we studied whether TREM2 influences glioma progression. We found a sex- dependent effect of TREM2: the glioma volume is significantly attenuated in TREM2- deficient male but not female mice injected with GL261-EGFP glioma cells. The accumulation of glioma-associated microglia/macrophages (GAMs) and vascularization is reduced in male TREM2-deficient mice. A transcriptomic analysis of glioma tissue revealed that TREM2 deficiency suppresses angiogenic genes and MHC clusters. In an organotypic slice model devoid of functional vascularization, the tumor size was not affected by TREM2-deficiency. In human resection samples from glioblastoma, TREM2 is upregulated in GAMs. Based on the TCGA and CGGA databases, the TREM2 expression levels are negatively correlated with survival. Thus, the TREM2-dependent crosstalk between GAMs and the vasculature formation promotes glioma growth. Graphic abstractTREM2-dependent crosstalk between glioma-associated microglia/macrophages and the vasculature formation promotes glioma growth in male glioma mouse model. Created with BioRender.com O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/540621v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@65bec7org.highwire.dtl.DTLVardef@1d00961org.highwire.dtl.DTLVardef@117ee5eorg.highwire.dtl.DTLVardef@227994_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Theranostic gold in a gold cage nanoparticle for photothermal ablation and photoacoustic imaging of skin and oral infections

AbstractBiofilms are structured communities of microbial cells embedded in a self-produced matrix of extracellular polymeric substances. Biofilms are associated with many health issues in humans, including chronic wound infections and tooth decay. Current antimicrobials are often incapable of disrupting the polymeric biofilm matrix and reaching the bacteria within. Alternative approaches are needed. Here, we describe a unique structure of dextran coated gold in a gold cage nanoparticle that enables photoacoustic and photothermal properties for biofilm detection and treatment. Activation of these nanoparticles with a near infrared laser can selectively detect and kill biofilm bacteria with precise spatial control and in a short timeframe. We observe a strong biocidal effect against both Streptococcus mutans and Staphylococcus aureus biofilms in mouse models of oral plaque and wound infections respectively. These effects were over 100 times greater than that seen with chlorhexidine, a conventional antimicrobial agent. Moreover, this approach did not adversely affect surrounding tissues. We conclude that photothermal ablation using theranostic nanoparticles is a rapid, precise, and non-toxic method to detect and treat biofilm-associated infections.

bioengineering↗

bioRxiv2023

Towards a human brain EV atlas: Characteristics of EVs from different brain regions, including small RNA and protein profiles

Extracellular vesicles (EVs) are released from different cell types in the central nervous system (CNS) and play roles in regulating physiological and pathological functions. Although brain-derived EVs (bdEVs) have been successfully collected from brain tissue, there is not yet a "bdEV atlas" of EVs from different brain regions. To address this gap, we separated EVs from eight anatomical brain regions of a single individual and subsequently characterized them by count, size, morphology, and protein and RNA content. The greatest particle yield was from cerebellum, while the fewest particles were recovered from the orbitofrontal, postcentral gyrus, and thalamus regions. EV surface phenotyping indicated that CD81 and CD9 were more abundant than CD63 for all regions. Cell-enriched surface markers varied between brain regions. For example, putative neuronal markers NCAM, CD271, and NRCAM were more abundant in medulla, cerebellum, and occipital regions, respectively. These findings, while restricted to tissues from a single individual, suggest that additional studies are merited to lend more insight into the links between EV heterogeneity and function in the CNS.

neuroscience↗

bioRxiv2023

Discovery and characterization of highly potent and selective covalent inhibitors of SARS-CoV-2 PLpro

Coronavirus infections, such as the global COVID-19 pandemic, have had a profound impact on many aspects of our daily life including working style, economy, and the healthcare system. To prevent the rapid viral transmission and speed up recovery from the infection, many academic organizations and industry research labs have conducted extensive research on discovering new therapeutic options for SARS-CoV-2. Among those efforts, RNA-dependent RNA polymerase (RdRp) inhibitors such as Remdesivir, Molnupiravir and 3CLpro inhibitor such as Nirmatrelvir (Paxlovid) have been widely used as the therapeutic options. Given the recent emergence of several new variants that caused a resurgence of the virus, it would be beneficial to discover more diverse therapeutic options with novel anti-viral mechanisms. In this regard, PLpro has been highlighted since it, along with 3CLpro, is one of the two most important proteases that are required for SARS-CoV-2 viral processing. While 3CLpro inhibitors were extensively investigated in the light of Emergency Use Authorizations of Nirmatrelvir, PLpro inhibitors have not been thoroughly investigated even preclinically. Thus, discovery efforts on antivirals acting against PLpro will be valuable. PLpro inhibitors may exert their activity by inhibiting viral replication and enhancing the host defense system through blocking virus-induced cell signaling events for evading host immune response. In this study, we report the discovery and development of two covalent irreversible PLpro inhibitors, HUP0109 and its deuterated analog DX-027, out of our quest for novel anti-COVID 19 therapeutic agents for the past two and half years. HUP0109 selectively targets the viral catalytic cleft of PLpro and covalently modifies its active site cysteine residue (C111). Promising results from preclinical evaluation suggest that DX-027 can be developed as a potential COVID-19 treatment.

pharmacology and toxicology↗

bioRxiv2023

DEGAP: Dynamic Elongation of a Genome Assembly Path

Genome assembly remains to be a major task in genomic research. Despite the development over the past decades of different assembler software programs and algorithms, it is still a great challenge to assemble a complete genome with no gaps. With the latest DNA Circular Consensus Sequencing (CCS) technology, several assembler programs now can build a genome from raw sequencing data to contigs, however, some complex sequence regions remain as unresolved gaps. Here, we present a novel gap-filling software DEGAP that can resolve gap regions in genomes by utilizing the dual advantages of accuracy and length of high-fidelity (HiFi) reads. DEGAP optimizes HiFi reads by identifying the differences between reads and provides GapFiller or CtgLinker modes to eliminate or shorten gaps in genomes. DEGAP adopts a cyclic elongation strategy that automatically and dynamically adjusts parameters according to the complexity of the sequences and selects the optimal extension path. DEGAP has already been successfully applied to decipher complex genomic regions in several projects and may be widely employed to generate more gap-free genomes.

bioinformatics↗

bioRxiv2023

CRACD suppresses neuroendocrinal plasticity of lung adenocarcinoma

Tumor cell plasticity contributes to intratumoral heterogeneity and therapy resistance. Through cell plasticity, lung adenocarcinoma (LUAD) cells transform into neuroendocrinal (NE) tumor cells. However, the mechanisms of NE cell plasticity remain unclear. CRACD, a capping protein inhibitor, is frequently inactivated in cancers. CRACD knock-out (KO) de-represses NE-related gene expression in the pulmonary epithelium and LUAD cells. In LUAD mouse models, Cracd KO increases intratumoral heterogeneity with NE gene expression. Single-cell transcriptomic analysis showed that Cracd KO-induced NE plasticity is associated with cell de-differentiation and activated stemness-related pathways. The single-cell transcriptomes of LUAD patient tumors recapitulate that the distinct LUAD NE cell cluster expressing NE genes is co-enriched with SOX2, OCT4, and NANOG pathway activation, and impaired actin remodeling. This study reveals an unexpected role of CRACD in restricting NE cell plasticity that induces cell de-differentiation, providing new insights into cell plasticity of LUAD.

cancer biology↗