Biology subjects

Wang, J. C.

Publications and source records attributed to Wang, J. C..

11 recordsLinked to original sources

bioRxiv2026

Cell-state-dependent responses to PLK1 inhibition reveal a non-canonical microtubule-endolysosomal vulnerability in quiescent leukemia stem cells

Relapse in cancer is frequently driven by therapy-resistant quiescent cancer stem cells. Conventional chemotherapy has been designed to target proliferating tumor cells and is generally presumed to be ineffective against non-cycling cancer stem cells. Using acute myeloid leukemia (AML) as a model, we challenge this prevailing view by showing that inhibition of the mitotic master regulator Polo-like kinase 1 (PLK1), a kinase extensively pursued for antiproliferative cancer therapy, unexpectedly eradicates quiescent leukemia stem cells (LSC) through a mechanism distinct from its canonical mitotic function. In proliferating AML cells, PLK1 inhibition (PLK1i) induced G2/M arrest and mitotic catastrophe. In contrast, quiescent LSC underwent apoptosis independent of mitotic arrest, revealing a cell-state-dependent mode of drug action. Mechanistically, PLK1i initiated a multi-step process through disruption of a previously unrecognized, stem cell-specific interaction between PLK1 and MAP1A, resulting in perturbed vesicle trafficking and endolysosomal homeostasis characterized by altered receptor internalization, vesicle accumulation and lysosomal dysfunction, ultimately culminating in apoptotic cell death. Combinatorial pharmacologic perturbation studies established microtubule regulation as a critical determinant of quiescent LSC survival, while ex vivo and in vivo assays demonstrated depletion of functionally-defined LSC following PLK1i. These findings identify a previously unrecognized role for PLK1 in intracellular trafficking and establish MAP1A-dependent control of vesicle homeostasis as a mechanistic determinant of cancer stem cell survival. More broadly, this study demonstrates that classical antimitotic compounds, including microtubule-targeting agents and PLK1 inhibitors, can eradicate both cycling leukemic blasts and quiescent LSC through distinct, cell state-dependent mechanisms, challenging proliferation-centric models of chemotherapy action.

cancer biology↗

bioRxiv2026

Scalable high-fidelity human vascularized cortical assembloids recapitulate neurovascular co-development and cell specialization

Human cortical development involves the coupling of neurogenesis and cerebrovascular growth. However, interactions between neural and vascular cells are largely missing in most brain organoids, which are crucial models for studying neurodevelopment and disease. Here, we establish vascularized cortical assembloids (vCAs) by fusing mesoderm-derived vascular organoids (VOs) with cortical organoids (COs). vCAs self-assemble lumenized networks of endothelial cells, pericytes, and perivascular fibroblasts that acquire blood-brain barrier (BBB) specialization and arteriovenous specification in vitro. Single-cell RNA-sequencing and immunofluorescence imaging revealed that vascularization improves neuroepithelial architecture, reduces hypoxia and apoptosis, expands cortical progenitor pools, and enhances neuronal maturation and connectivity compared with COs. Moreover, atlas-level integration with human neurodevelopmental tissue and cross-protocol benchmarking demonstrate superior transcriptional concordance, especially for vascular cell and glial populations, relative to existing approaches. This scalable and reproducible platform improves fidelity and throughput for modeling human neurovascular co-development and enables systematic studies across brain regions and diseases using engineered or patient-derived iPSCs.

developmental biology↗

bioRxiv2025

A Rapid Gene Expression Profiler Classifies AML Tumor Responsiveness to Standard Therapies

The emergence of transcriptional signatures that define cell types and pathways has made it possible to guide cancer therapy selection through gene expression profiling. We developed a rapid qPCR-based platform to profile cell state, stemness, and BCL2 family gene expression as a companion diagnostic test for acute myeloid leukemia (AML). We validated the stability and utility of the signatures across multiple measurement platforms and using patient samples from two centers. Integrating these signatures with clinical features enables an expedient means to predict the likelihood of patient responses to two standard-of-care therapies: intensive chemotherapy and hypomethylating agent plus venetoclax (HMA+Ven). For patients treated with HMA+Ven, expression levels of the promonocyte-like signature and BCL2 add predictive value for response and overall survival in multivariable models that include genetic features. The incorporation of the rapid profiler into the prospective evaluation of newly diagnosed AML patients may enhance treatment stratification and improve outcomes.

cancer biology↗

bioRxiv2024

Genomic Epidemiology of Monkeypox Virus During the 2022 Outbreak in New York City

New York City (NYC) was one of the hotspots of monkeypox virus (MPXV) infections in the United States during the multi-country mpox outbreak in 2022. This study used the most comprehensive dataset to date to investigate the genomic characteristics of MPXV in NYC. We performed Nextclade lineage assignment, phylogenetic and mutational analyses on 1,138 specimens from 748 individuals at the NYC Public Health Lab in the context of 2,968 MPXV sequences sampled globally. Nextclade lineage assignment showed B.1.12 as a NYC specific lineage and phylogenetic analysis showed NYC and North America specific clades. The majority of mutations showed signatures of APOBEC3 activity. When looking at the intra-host genomic diversity for MPXV, distinct MPXV genomic profiles were observed in 6.4% of individuals with multiple sampled specimens, with at least 4.2% of NYC cases due to multiple MPXV infections from distinct viral strains. Further, 13% of the sequences in infected patients had a lack of concordance between epidemiologic and genetic linkages. This study identified NYC-specific MPXV genomic profiles and provided a conservative estimate of simultaneous infections with multiple MPXV variants, likely due to behavioral risk factors during the peak of the outbreak in July 2022. Improving concordance between genomic and epidemiological clusters for mpox investigations may require expanding partnerships with testing labs, clinics, and community groups to enhance the representativeness of MPXV samples that are available for sequencing.

genomics↗

bioRxiv2024

FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human hematopoietic stem cells

Leukemic stem cells (LSCs) fuel acute myeloid leukemia (AML) growth and relapse, but therapies tailored towards eradicating LSCs without harming healthy hematopoietic stem cells (HSCs) are lacking. FLT3 is considered an important therapeutic target due to frequent mutation in AML and association with relapse. However, there has been limited clinical success with FLT3 targeting, suggesting either that FLT3 is not a vulnerability in LSC, or that more potent inhibition is required, a scenario where HSC toxicity could become limiting. We tested these possibilities by ablating FLT3 using CRISPR/Cas9-mediated FLT3 knock-out (FLT3-KO) in human LSCs and HSCs followed by functional xenograft assays. FLT3-KO in LSCs from FLT3-ITD mutated, but not FLT3-WT AMLs, resulted in short-term leukemic grafts of FLT-3-KO edited cells that disappeared by 12 weeks. By contrast, FLT3-KO in HSCs from fetal liver, cord blood and adult bone marrow did not impair multilineage hematopoiesis in primary and secondary xenografts. Our study establishes FLT3 as an ideal therapeutic target where ITD+ LSC are eradicated upon FLT3 deletion, while HSCs are spared. These findings support the development of more potent FLT3-targeting drugs or gene-editing approaches for LSC eradication to improve clinical outcomes. KEY POINTSThe FLT3 gene is essential for ITD-mutated leukemic stem cells (LSCs) to establish and propagate leukemia. Normal human hematopoietic stem cells (HSCs) do not require FLT3 to engraft and sustain hematopoiesis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/601363v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@b77f56org.highwire.dtl.DTLVardef@109011dorg.highwire.dtl.DTLVardef@282e04org.highwire.dtl.DTLVardef@1e51e3b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Foxp- and Skor-family proteins control differentiation of Purkinje cells from Ptf1a and Neurogenin1-expressing progenitors in zebrafish

Cerebellar neurons such as Purkinje cells (PCs) and granule cells (GCs) are differentiated from neural progenitors expressing proneural genes. Zebrafish mutants of proneural genes ptf1a and neurogenin1 showed a reduction or loss of PCs, GABAergic interneurons (INs), and reduced expression of GC progenitor genes atoh1a/b/c. Lineage tracing revealed that the ptf1a-expressing progenitors gave rise to PCs, INs, and a part of GCs in zebrafish. These data indicate that the ptf1a/neurognin1-expressing neural progenitors can generate a variety of cerebellar neurons. In this study, we found that genes encoding transcriptional regulators Foxp1b and Foxp4, as well as Skor1b and Skor2, which are reportedly expressed in PCs, were not expressed in ptf1a;neurogenin1 mutants. foxp1b;foxp4 mutants showed a strong reduction in PCs, while skor1b;skor2 mutants completely lacked PCs but instead displayed an increase in immature GCs. Misexpression of skor2 in GC progenitors expressing atoh1c suppressed GC fate. These data indicate that Foxp1b/4 and Skor1b/2 function as key transcriptional regulators in the initial step of PC differentiation from ptf1a/neurogenin1-expressing neural progenitors, while Skor1b and Skor2 control PC differentiation by suppressing their differentiation into GCs.

developmental biology↗

bioRxiv2022

A Novel Chronic in vivo Oral Cadmium Exposure-Washout Mouse Model for Studying Cadmium Toxicity and Complex Diabetogenic Effects

Type II diabetes mellitus (T2DM) is characterized by insulin resistance, {beta}-cell dysfunction and hyperglycemia. In addition to well known risk factors such as lifestyle and genetic risk score, accumulation of environmental toxicants in organs relevant to glucose metabolism is increasingly recognized as additional risk factors for T2DM. Here, we describe the development of an in vivo oral cadmium (Cd) exposure model. It was shown that oral Cd exposure in drinking water followed by washout and high fat diet (HFD) in C57BL/6N mice results in islet Cd bioaccumulation comparable to that found in native human islets while mitigating the anorexic effects of Cd to achieve the same weight gain required to induce insulin resistance as in Cd naive control mice. Inter individual variation in plasma glucose and insulin levels as well as islet Cd bioaccumulation was observed in both female and male mice. Regression analysis showed an inverse correlation between islet Cd level and plasma insulin following a glucose challenge in males but not in females. This finding highlights the need to account for inter individual target tissue Cd concentrations when interpreting results from in vivo Cd exposure models. No effect of Cd on insulin secretion was observed in islets ex vivo, highlighting differences between in vivo and ex vivo cadmium exposure models. In summary, our oral in vivo Cd exposure-washout with HFD model resulted in islet Cd bioaccumulation that is relevant in the context of environmental cadmium exposure in humans. Here, we showed that islet Cd bioaccumulation is associated with complex cadmium-mediated changes in glucose clearance and {beta}-cell function. The model described here will serve as a useful tool to further examine the relationship between Cd exposure, islet Cd bioaccumulation, dysglycemia and their underlying mechanisms.

pharmacology and toxicology↗

bioRxiv2021

A B cell actomyosin arc network couples integrin co-stimulation to mechanical force-dependent immune synapse formation

B-cell activation and immune synapse (IS) formation with membrane-bound antigens are actin-dependent processes that scale positively with the strength of antigen-induced signals. Importantly, ligating the B-cell integrin, LFA-1, with ICAM-1 promotes IS formation when antigen is limiting. Whether the actin cytoskeleton plays a specific role in integrin-dependent IS formation is unknown. Here we show using super-resolution imaging of mouse primary B cells that LFA-1: ICAM-1 interactions promote the formation of an actomyosin network that dominates the B-cell IS. This network is created by the formin mDia1, organized into concentric, contractile arcs by myosin 2A, and flows inward at the same rate as B-cell receptor (BCR): antigen clusters. Consistently, individual BCR microclusters are swept inward by individual actomyosin arcs. Under conditions where integrin is required for synapse formation, inhibiting myosin impairs synapse formation, as evidenced by reduced antigen centralization, diminished BCR signaling, and defective signaling protein distribution at the synapse. Together, these results argue that a contractile actomyosin arc network plays a key role in the mechanism by which LFA-1 co-stimulation promotes B-cell activation and IS formation.

immunology↗

bioRxiv2020

Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease defined by motor neuron (MN) loss. Multiple genetic risk factors have been identified, implicating RNA and protein metabolism and intracellular transport, among other biological mechanisms. To achieve a systems-level understanding of the mechanisms governing ALS pathophysiology, we built gene co-expression networks using RNA-sequencing data from control human spinal cord samples, identifying 13 gene co-expression modules, each of which represents a distinct biological process or cell type. Analysis of four RNA-seq datasets from a range of ALS disease-associated contexts reveal dysregulation in numerous modules related to ribosomal function, wound response, and leukocyte activation, implicating astrocytes, oligodendrocytes, endothelia, and microglia in ALS pathophysiology. To identify potentially causal processes, we partitioned heritability across the genome, finding that ALS common genetic risk is enriched within two specific modules, SC.M4, representing genes related to RNA processing and gene regulation, and SC.M2, representing genes related to intracellular transport and autophagy and enriched in oligodendrocyte markers. Top hub genes of this module include ALS-implicated risk genes such as KPNA3, TMED2, and NCOA4, the latter of which regulates ferritin autophagy, implicating this process in ALS pathophysiology. These unbiased, genome-wide analyses confirm the utility of a systems approach to understanding the causes and drivers of ALS.

genomics↗

bioRxiv2019

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease and progressive supranuclear palsy converge on altered glial regulation

Parkinsons disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD, we fine-mapped the 17q21.31 locus in order to identify novel mechanisms conferring risk for the disease. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble -synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with -synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

neuroscience↗

bioRxiv2019

Integrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism

Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous neurodevelopmental disorder. Despite this heterogeneity, previous studies have shown patterns of molecular convergence in post-mortem brain tissue from autistic subjects. Here, we integrate genome-wide measures of mRNA expression, miRNA expression, DNA methylation, and histone acetylation from ASD and control brains to identify a convergent molecular subtype of ASD with shared dysregulation across both the epigenome and transcriptome. Focusing on this convergent subtype, we substantially expand the repertoire of differentially expressed genes in ASD and identify a component of upregulated immune processes that are associated with hypomethylation. We utilize eQTL and chromosome conformation datasets to link differentially acetylated regions with their cognate genes and identify an enrichment of ASD genetic risk variants in hyperacetylated noncoding regulatory regions linked to neuronal genes. These findings help elucidate how diverse genetic risk factors converge onto specific molecular processes in ASD.

genomics↗