Biology subjects

Wang, W.-L.

Publications and source records attributed to Wang, W.-L..

11 recordsLinked to original sources

bioRxiv2026

Dual Traditional Chinese Medicine-Preconditioned Stem Cell Secretomes in Coaxial Electrospun Nanofibers Synergistically Accelerate Diabetic Wound Regeneration

Chronic diabetic wounds resist healing due to impaired angiogenesis, stalled cellular migration, and persistent inflammation, a challenge further compounded by the rapid degradation of therapeutic growth factors in the proteolytic wound bed. To overcome this, Traditional Chinese Medicine (TCM) compounds are employed not as standalone drugs, but as biomolecular stimuli to precondition the secretome of Wharton's Jelly-derived mesenchymal stem cells (WJMSCs). To overcome these critical translational barriers, this study engineers a core-shell coaxial electrospun nanofibrous scaffold (polyvinyl alcohol core/gelatin shell) designed for the stabilizing and sustained dual-delivery of biologics. We introduce a novel synergistic payload with WJMSCs conditioned medium (WJMSCs-CM) uniquely primed by two specific chinese herbal compounds, Astragaloside IV (AS-IV) and Formononetin (FMN). This core-shell architecture provides native-like contact guidance for cells while converting conventional burst release into a sustained, weeks-long elution. In vitro, this functionalized scaffold restores Akt/eNOS signaling, rescues cellular viability, and promotes robust tube formation in high-glucose-stressed fibroblasts and endothelial cells. In vivo, within an STZ-induced diabetic rat model, the application of this WJMSCs-CM-loaded coaxial scaffold actively inhibits early inflammation and comprehensively accelerates healing, driving near-complete wound closure (98.2 by day 21), mature collagen deposition, and hair follicle neogenesis. Ultimately, this bio-instructive platform successfully integrates physical structural cues with sustained biochemical signaling, offering a potent, multifaceted strategy for chronic wound regeneration.

bioengineering↗

bioRxiv2026

Spatially-resolved single cell atlas of liposarcoma reveals lineage hierarchies, immune niches, and regulatory circuits

Well-differentiated and dedifferentiated liposarcoma (WDLPS and DDLPS) exhibit markedly different clinical behaviors, with DDLPS showing greater aggressiveness, higher recurrence and metastasis rates, and worse outcomes. Using single-nucleus multiome sequencing, epigenomic profiling, and spatial transcriptomics, we characterized cellular and epigenetic heterogeneity between these subtypes at single-cell and spatial resolution. We found distinct phenotypic states reflecting altered lineage differentiation and plasticity: DDLPS is dominated by early-differentiated progenitor-like cells, sclerotic WDLPS displays broader mesenchymal lineage plasticity, and adipocytic WDLPS contains abundant committed adipocytes. The DDLPS immune microenvironment was dominated by immunosuppressive macrophages, whereas WDLPS harbored more T cells and inflammatory macrophages. Notably, sclerotic WDLPS displayed intermediate cellular and molecular features, suggesting it may represent a distinct WDLPS subtype. Importantly, we identified novel gene regulatory circuits underlying each state, including FABP4/PPARG programs in adipocytic WDLPS, GLI2/TCF7L2/RBPJ/KLF7 programs in sclerotic WDLPS, and KLF7/FOSL2/SP3/GLI2/RBPJ programs in DDLPS. H3K27ac-marked enhancers were enriched near adipocytic marker genes in WDLPS and mesenchymal markers in DDLPS. Together, these findings reveal the cellular heterogeneity of tumor and immune compartments across liposarcoma subtypes and identify regulatory programs driving their differentiation states. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/713651v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@1c84ee1org.highwire.dtl.DTLVardef@1b2ad42org.highwire.dtl.DTLVardef@18ce5a6org.highwire.dtl.DTLVardef@138f615_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

ATRX Loss Predicts Poor Outcomes and Reveals a Therapeutic Vulnerability to TEAD Inhibition in Soft Tissue Sarcomas

ATRX is one of the most frequently altered genes in sarcoma and encodes an ATP-dependent chromatin remodeler implicated in maintaining heterochromatin. However, ATRX alterations have not been leveraged for sarcoma treatment. We observed loss of ATRX protein in 14% of soft tissue leiomyosarcoma (STLMS, n =127), 53% of uterine leiomyosarcoma (ULMS, n = 95), 37% of undifferentiated pleomorphic sarcoma (UPS, n = 82), and 8% of dedifferentiated liposarcoma (DDLPS, n = 84). ATRX loss was associated with significantly worse outcomes in ULMS, UPS, and DDLPS. ATRX knockout in sarcoma cells increased proliferation in cooperation with TP53 deletion. ATRX knockout led to chromatin de-repression and enrichment of PRDM4 and NFIX transcription factor (TF) motifs. PRDM4 and NFIX knockdown in ATRX-mutant sarcoma lines resulted in reduced proliferation and invasion suggesting epistatic relationship. Consistent with the known functional relationship between PRMD4 and YAP1, we observed that ATRX/TP53 KO cells were more sensitive to the TEAD inhibitor VT103 compared to TP53 KO and ATRX WT controls. Overall, our results identify ATRX loss as a prognostic factor of worse outcomes, implicate the ATRX-PRDM4-YAP1 axis as a novel underlying mechanism, and suggest use of TEAD inhibition as a potential therapeutic strategy for ATRX-deficient sarcomas. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=45 SRC="FIGDIR/small/689992v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@a759ecorg.highwire.dtl.DTLVardef@100c580org.highwire.dtl.DTLVardef@1a675c9org.highwire.dtl.DTLVardef@17f1f91_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Salinity impacted microbial carbonate precipitation mechanisms of modern microbialites in peritidal zone

Microbialites, ancient records of microbial activity, serve as significant indicators of environmental change. This study examined microbialites from the peritidal zone of three tide pools at Fongchueisha, Hengchun, Taiwan, to investigate the impact of salinity on microbial community composition and carbonate precipitation mechanisms. Microbial samples were collected across varying salinity gradients over multiple timepoints and analyzed using next-generation sequencing of bacterial 16S and eukaryotic 18S rRNA genes. Our findings reveal that the microbial communities in higher salinity environments exhibited significant shifts, with increased relative abundance of ureolytic bacteria and ammonifying microorganisms, such as Myxococcota and Actinobacteriota. This suggests the presence of diverse microbial carbonate precipitation mechanisms beyond photosynthesis, including ureolysis and ammonification. Furthermore, our results show that changes in the composition of cyanobacteria and diatoms were influenced by salinity, with heterocystous cyanobacteria (e.g., Nostocales) dominating low-salinity environments, and non-heterocystous cyanobacteria (e.g., Synechococcales) prevailing in higher salinity environments. Functional predictions reveal that microbial communities in high-salinity environments were enriched in anaerobic metabolic pathways, including pyruvate fermentation and the urea cycle. These findings highlight the significant role of salinity in influencing microbial composition and metabolic pathways, shaping carbonate precipitation processes in microbialites. ImportanceThe study focuses on the impact of environmental salinity on microbial community composition and carbonate precipitation mechanisms within modern microbialites, based on an analysis of samples from three tide pools with different salinity levels collected at five time points throughout the year. Using next-generation sequencing of bacterial 16S and eukaryotic 18S rRNA genes, we identified key shifts in microbial communities along salinity gradients and explored diverse microbial processes involved in carbonate precipitation. This work enhances our understanding of microbial ecosystems within modern microbialites and their response to environmental changes. Additionally, our study provides insight into ancient biogeochemical processes, with implications for interpreting microbial metabolism in carbonate precipitation across different salinity regimes.

microbiology↗

bioRxiv2023

A Whole-Cell Screening Platform to Discover Cell Adhesion Molecules that Enable Programmable Bacterial Cell-Cell Adhesion

Developing programmable bacterial cell-cell adhesion is of significant interest due to its versatile applications. Current methods that rely on presenting cell adhesion molecules (CAMs) on bacterial surfaces are limited by the lack of a generalizable strategy to identify such molecules targeting bacterial membrane proteins in their natural states. Here, we introduce a whole-cell screening platform designed to discover CAMs targeting bacterial membrane proteins within a synthetic bacteria-displayed nanobody library. Leveraging the potency of the bacterial type IV secretion system--a contact-dependent DNA delivery nanomachine--we have established a positive feedback mechanism to selectively enrich for bacteria displaying nanobodies that target antigen-expressing cells. Our platform successfully identified functional CAMs capable of recognizing three distinct outer membrane proteins (TraN, OmpA, OmpC), demonstrating its efficacy in CAM discovery. This approach holds promise for engineering bacterial cell-cell adhesion, such as targeted antimicrobial interventions in the microbiome by deploying programmed inhibitor cells.

microbiology↗

bioRxiv2022

Whether the ADP-ribosyltransferase activity of Ta-sro1, a noncanonical PARP protein, contributes to its function in salinity-stress tolerance?

ADP-ribosylation mediated by ADP-ribosyltransferases (ARTs) is an intricate modification that regulates diverse cellular processes including DNA repair, chromatin remodeling and gene transcription responding to stresses. In addition to the canonical poly(ADP-ribose) polymerases (PARPs), plant specific SRO (Similar to RCD One) family also contain the catalytic core of the PARP domain. However, whether the PARP domains in SROs execute the ART function is still under debate. In 2014, we reported a wheat SRO, Ta-sro1, had the ADP-ribosyltransferase activity and enhanced wheat seedling growth and abiotic stress resistance, however, a recent work by Vogt et al. showed that Ta-sro1 without ADP-ribosyltransferase activity. Based on the recent progress on PARPs and SROs in relation to ADP-ribosyltransferase activity, along with our former and recent evolving results, we argued that Ta-sro1 is a non-canonical ADP-ribosyltransferase with the enzymatic activity. Although we have revealed the novel mechanism of Ta-sro1 regulate redox homeostasis and enhance salinity stress tolerance through interacting with TaSIP1, it is of interest to further clarify whether and how the enzymatic activity of Ta-sro1 responsible for the salinity tolerance of wheat. Our study raises some interesting points and caveats that helpful for understanding the research progresses and debates about the enzymatic activity of SROs.

molecular biology↗

bioRxiv2022

The Androgen Receptor: A Therapeutic Target in Desmoplastic Small Round Cell Sarcoma

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have immediate clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer. ONE SENTENCE SUMMARYWe demonstrate that DSRCT, an aggressive pediatric cancer, is an AR-driven malignancy capable of responding to androgen deprivation therapy.

cancer biology↗

bioRxiv2021

New cellular models of undifferentiated pleomorphic sarcoma and malignant peripheral nerve sheath tumor

Undifferentiated pleomorphic sarcoma (UPS) and malignant peripheral nerve sheath tumor (MPNST) are aggressive soft tissue sarcomas that do not respond well to current treatment modalities. The limited availability of UPS and MPNST cell lines makes it challenging to identify potential therapeutic targets in a laboratory setting. Understanding the urgent need for improved treatments for these tumors and the limited cellular models led us to generate additional cell lines to study these rare cancers further. Patient-derived tumors were used to establish 5 new UPS models, including one radiation-associated UPS--UPS060.1, UPS271.1, UPS511, UPS0103, and RIS620--and 3 new models of MPNST--MPNST007, MPNST3813E, and MPNST4970. This study examined the utility of the new cell lines as sarcoma models by assessing tumorigenic potential and mutation status for known sarcoma-related genes. All the cell lines formed colonies and migrated in vitro. The in vivo tumorigenic potential of each cell line was determined by either subcutaneous injection of cells or implantation of tumor tissue into immunocompromised mice. UPS060.1, UPS271.1, and UPS511 cells formed tumors in mice upon subcutaneous injection. UPS0103 and RIS620 tumor implants formed tumors in vivo, as did MPNST007 and MPNST3813E tumor implants. Mutation analysis of a panel of genes frequently mutated in sarcomas showed that two of the three MPNST cell lines had NF1 mutations. Two of the three MPNST cell lines had mutations in polycomb repressive complex 2 members. These new cellular models provide the scientific community with powerful tools for detailed studies of sarcomagenesis and investigate novel therapies for UPS and MPNST.

cancer biology↗

bioRxiv2020

Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity

Monitoring the mutation dynamics of SARS-CoV-2 is critical for the development of effective approaches to contain the pathogen. By analyzing 106 SARS-CoV-2 and 39 SARS genome sequences, we provided direct genetic evidence that SARS-CoV-2 has a much lower mutation rate than SARS. Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history. The discrepant phylogenies for the spike protein and its receptor binding domain proved a previously reported structural rearrangement prior to the emergence of SARS-CoV-2. Despite that we found the spike glycoprotein of SARS-CoV-2 is particularly more conserved, we identified a receptor binding domain mutation that leads to weaker ACE2 binding capability based on in silico simulation, which concerns a SARS-CoV-2 sample collected on 27th January 2020 from India. This represents the first report of a significant SARS-CoV-2 mutant, and requires attention from researchers working on vaccine development around the world. HighlightsO_LIBased on the currently available genome sequence data, we provided direct genetic evidence that the SARS-COV-2 genome has a much lower mutation rate and genetic diversity than SARS during the 2002-2003 outbreak. C_LIO_LIThe spike (S) protein encoding gene of SARS-COV-2 is found relatively more conserved than other protein-encoding genes, which is a good indication for the ongoing antiviral drug and vaccine development. C_LIO_LIMinimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history. C_LIO_LIWe confirmed a previously reported rearrangement in the S protein arrangement of SARS-COV-2, and propose that this rearrangement should have occurred between human SARS-CoV and a bat SARS-CoV, at a time point much earlier before SARS-COV-2 transmission to human. C_LIO_LIWe provided first evidence that a mutated SARS-COV-2 with reduced human ACE2 receptor binding affinity have emerged in India based on a sample collected on 27th January 2020. C_LI

evolutionary biology↗

bioRxiv2019

Bivalent and Broad Chromatin Domains Regulate Pro-metastatic Drivers in Melanoma

Chromatin deregulation is an emerging hallmark of cancer. However, the extent of epigenetic aberrations during tumorigenesis and their relationship with genetic aberrations are poorly understood. Using ChIP-sequencing for enhancers (H3K27ac and H3K4me1), promoters (H3K4me3), active transcription (H3K79me2) and polycomb (H3K27me3) or heterochromatin (H3K9me3) repression we generated chromatin state profiles in metastatic melanoma using 46 tumor samples and cell lines. We identified a strong association of NRAS, but not BRAF mutations, with bivalent states harboring H3K4me3 and H3K27me3 marks. Importantly, the loss and gain of bivalent states occurred on important pro-metastasis regulators including master transcription factor drivers of mesenchymal phenotype including ZEB1, TWIST1, SNAI1 and CDH1. Unexpectedly, a subset of these and additional pro-metastatic drivers (e.g. POU3F2, SOX9 and PDGFRA) as well as melanocyte-specific master regulators (e.g. MITF, ZEB2, and TFAP2A) were regulated by exceptionally wide H3K4me3 domains that can span tens of thousands of kilobases suggesting roles of this new epigenetic element in melanoma metastasis. Overall, we find that BRAF, NRAS and WT melanomas may use bivalent states and broad H3K4me3 domains in a specific manner to regulate pro-metastatic drivers. We propose that specific epigenetic traits - such as bivalent and broad domains - get assimilated in the epigenome of pro-metastatic clones to drive evolution of cancer cells to metastasis.

cancer biology↗

bioRxiv2018

Enhancer Reprogramming Confers Dependence on Glycolysis and IGF signaling in KMT2D Mutant Melanoma

Epigenetic modifiers have emerged as important regulators of tumor progression. We identified histone methyltransferase KMT2D as a potent tumor-suppressor through an in vivo epigenome-focused pooled RNAi screen in melanoma. KMT2D harbors frequent somatic point mutations in multiple tumor types. How these events contribute to tumorigenesis and whether they impart therapeutic vulnerability are poorly understood. To address these questions, we generated a genetically engineered mouse model of melanoma based on conditional and melanocyte-specific deletion of KMT2D. We demonstrate KMT2D as a bona fide tumor suppressor which cooperates with activated BRAF. KMT2D-deficient tumors showed substantial reprogramming of key metabolic pathways including glycolysis. Glycolysis enzymes, intermediate metabolites and glucose consumption rate were aberrantly upregulated in KMT2D mutant cells. The pharmacological inhibition of glycolysis reduced proliferation and tumorigenesis preferentially in KMT2D mutant cells. Mechanistically, KMT2D loss caused drastic reduction of H3K4me1-marked active enhancer states. Loss of distal enhancer and subsequent reduction in expression of IGFBP5 activated IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating increased usage of glycolysis pathway for enhanced biomass needs via enhancer reprogramming. Our data imply that inhibition of glycolysis or IGFR pathway could be a potential therapeutic strategy in KMT2D mutant tumors.

cancer biology↗