Wenhuo Hu - Academia.edu (original) (raw)

Papers by Wenhuo Hu

Journal of Clinical Oncology, 2022

564 Background: Upper tract urothelial carcinoma (UTUC) is an aggressive disease that is risk-str... more 564 Background: Upper tract urothelial carcinoma (UTUC) is an aggressive disease that is risk-stratified by clinicopathological factors due to an incomplete understanding of its molecular features. Thus, we performed transcriptomic profiling of UTUC tumors from radical nephroureterectomy specimens and compared their molecular characterization to survival outcomes. Methods: 100 UTUC tumors from 100 patients were subject to RNA sequencing and a hybridization capture-based assay for deep sequencing of cancer-associated genes, followed by unsupervised nonnegative matrix factorization clustering based on the top 10% of variant genes. Gene Set Enrichment and immune deconvolution analyses assessed for differences in the tumor microenvironments (TME) between clusters. Results: Consensus clustering analysis identified 5 biologically distinct clusters (Cluster 1 (C1) = 17, C2 = 18, C3 = 30, C4 = 11, and C5 = 24 patients), which were associated with significant differences in disease-free (DFS...

Journal of Urology, 2020

INTRODUCTION AND OBJECTIVE: Epigenetic deregulation is deeply implicated in the pathogenesis of b... more INTRODUCTION AND OBJECTIVE: Epigenetic deregulation is deeply implicated in the pathogenesis of bladder cancer (BC). Lysine (K)-specific demethylase 6A (KDM6A) is a histone modifier frequently mutated in BC. However, the molecular mechanisms of how KDM6A deficiency contributes to BC development remains largely unknown. We hypothesized that clarification of the pathogenic mechanisms underlying Kdm6a-mutated BC can help in designing new anti-cancer therapies. METHODS: To address this issue, we generated mice lacking Kdm6a in the urothelium and crossed them with mice heterozygous for p53, whose mutation/deletion significantly overlaps with the Kdm6a mutation in muscle-invasive BC (MIBC). In addition, N-butyl-N-(4hydroxybutyl) nitrosamine (BBN), a cigarette smoke-like mutagen, was used as a tumor-promoting agent. Isolated urothelia were subjected to phenotypical, pathological, molecular and cellular analyses. The clinical relevance of our findings was further analyzed using genomic and clinical data of patients with MIBC. RESULTS: We found that Kdm6a deficiency activated proinflammatory cytokines/chemokines, promoted M2 macrophage polarization, increased cancer stem cells and caused BC in cooperation with p53 dysfunction. We also found that BBN treatment significantly enhances the expression of proinflammatory molecules and accelerates disease development. Human BC samples with decreased Kdm6a expression also showed activated proinflammatory pathways. Notably, dual inhibition of interleukin-6 and chemokine (C-C motif) ligand 2, upregulated in response to Kdm6a deficiency, efficiently suppressed Kdm6a-deficient BC cell growth. CONCLUSIONS: Our findings provide insights into multistep carcinogenic processes of BC and suggest molecular targeted therapeutic approaches for BC patients with Kdm6a dysfunction.

470Background: Up to 25% of tumors are of pure variant or mixed urothelial and variant histology.... more 470Background: Up to 25% of tumors are of pure variant or mixed urothelial and variant histology. The presence of variant histology may be associated with more advanced stage at presentation and a ...

Nature Communications, 2021

Cancers develop from the accumulation of somatic mutations, yet it remains unclear how oncogenic ... more Cancers develop from the accumulation of somatic mutations, yet it remains unclear how oncogenic lesions cooperate to drive cancer progression. Using a mouse model harboring NRasG12D and EZH2 mutations that recapitulates leukemic progression, we employ single-cell transcriptomic profiling to map cellular composition and gene expression alterations in healthy or diseased bone marrows during leukemogenesis. At cellular level, NRasG12D induces myeloid lineage-biased differentiation and EZH2-deficiency impairs myeloid cell maturation, whereas they cooperate to promote myeloid neoplasms with dysregulated transcriptional programs. At gene level, NRasG12D and EZH2-deficiency independently and synergistically deregulate gene expression. We integrate results from histopathology, leukemia repopulation, and leukemia-initiating cell assays to validate transcriptome-based cellular profiles. We use this resource to relate developmental hierarchies to leukemia phenotypes, evaluate oncogenic cooper...

Experimental Hematology, 2018

We present a framework for the construction of solvable models of optical settings with genuinely... more We present a framework for the construction of solvable models of optical settings with genuinely twodimensional landscapes of refractive index. Solutions of the associated non-separable Maxwell equations in paraxial approximation are found using the time-dependent supersymmetry. We discuss peculiar theoretical aspects of the construction. In particular, we focus on the existence of localized solutions specific for the new systems. Sufficient conditions for their existence are discussed. Localized solutions vanishing for large | x|, which we call light dots, as well as the guided modes that vanish exponentially outside the wave guides, are constructed. We consider different definitions of the parity operator and analyze general properties of the PTsymmetric systems, e.g. presence of localized states or existence of symmetry operators. Despite the models with parity-time symmetry are of the main concern, the proposed framework can serve for construction of non-PT-symmetric systems as well. We explicitly illustrate the general results on a number of physically interesting examples, e.g. wave guides with periodic fluctuation of refractive index or with a localized defect, curved wave guides, two coupled wave guides or a uniform refractive index system with a localized defect.

Journal of Experimental Medicine, 2013

Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of hu... more Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel...

Experimental Hematology, 2013

Journal of Experimental Medicine, 2014

Hematopoietic stem cells (HSCs) are heterogeneous with respect to their self-renewal, lineage, an... more Hematopoietic stem cells (HSCs) are heterogeneous with respect to their self-renewal, lineage, and reconstitution potentials. Although c-Kit is required for HSC function, gain and loss-of-function c-Kit mutants suggest that even small changes in c-Kit signaling profoundly affect HSC function. Herein, we demonstrate that even the most rigorously defined HSCs can be separated into functionally distinct subsets based on c-Kit activity. Functional and transcriptome studies show HSCs with low levels of surface c-Kit expression (c-Kitlo) and signaling exhibit enhanced self-renewal and long-term reconstitution potential compared with c-Kithi HSCs. Furthermore, c-Kitlo and c-Kithi HSCs are hierarchically organized, with c-Kithi HSCs arising from c-Kitlo HSCs. In addition, whereas c-Kithi HSCs give rise to long-term lymphomyeloid grafts, they exhibit an intrinsic megakaryocytic lineage bias. These functional differences between c-Kitlo and c-Kithi HSCs persist even under conditions of stress...

The Journal of Urology, 2021

INTRODUCTION AND OBJECTIVE:Forkhead Box A1 (FOXA1) is a pioneer transcription factor (TF) critica... more INTRODUCTION AND OBJECTIVE:Forkhead Box A1 (FOXA1) is a pioneer transcription factor (TF) critical in epigenetic regulation of chromatin state and cell fate determination. Reduced FOXA1 is an indep...

Annals of the Rheumatic Diseases

ObjectivesOsteoarthritis (OA) is the most common joint disease; however, the indeterminate nature... more ObjectivesOsteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA.MethodsBiochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importan...

Journal of Clinical Investigation

Protein & Cell

designed and performed experiments, collected and analyzed data, and wrote the paper. A. Hettingh... more designed and performed experiments, collected and analyzed data, and wrote the paper. A. Hettinghouse assisted with experiments and editing the manuscript. W. Hu performed the flow cytometry analysis. J.Q. Wang, Z.N. Lei and Z.S. Chen performed the in silico docking simulations. K. A. Stapleford performed antiviral assay and also editing the manuscript. C. J. Liu designed and supervised this study, analyzed data, and co-wrote and edited the manuscript.

Molecular Cancer Research

Forkhead Box A1 (FOXA1) is a pioneer transcription factor critical in epigenetic regulation of ch... more Forkhead Box A1 (FOXA1) is a pioneer transcription factor critical in epigenetic regulation of chromatin and cell fate determination. Reduced FOXA1 expression is an independent predictor of poor overall survival in bladder cancer patients. However, the impact of FOXA1 loss on chromatin epigenetics in bladder cancer is unknown. Therefore, we determined the impact of FOXA1 knock out (KO) on epigenetic modification of chromatin and associated gene expression. We identified 8,230 differentially expressed genes following FOXA1 KO. Surprisingly, Gene Set Enrichment Analysis (GSEA) identified IFNɑ/ɣ gene expression signatures as enriched following FOXA1 KO. FOXA1 KO induced both increased and decreased numbers of histone 3 lysine 27 acetylation (H3K27ac) sites throughout the genome. As expected, the majority of differences in H3K27ac across genomic areas in FOXA1 KO cells is mapped to intergenic and intronic regions where enhancers reside. In addition, a subset of differential H3K27ac leve...

Nature Communications

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extra... more Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resi...

Journal of Clinical Oncology

529 Background: Large-scale efforts have sought to define the genomic landscape of urothelial car... more 529 Background: Large-scale efforts have sought to define the genomic landscape of urothelial carcinomas of the bladder with the goal of identifying novel therapeutic targets. Many bladder cancers harbor mutations in genes that regulate chromatin state, such as KDM6A, ARID1A and KMT2D. There remains uncertainty as to the timing at which alterations in chromatin modifying genes (CMG) arise during the evolution of urothelial cancer. Methods: We leveraged a prospective genomic profiling initiative to characterize driver alterations in urothelial cancer. To define the timing at which mutations arose during disease pathogenesis, we performed whole exome (WES) or targeted sequencing analysis of matched pairs of primary and metastatic tumors. Results: CMG mutations were identified in 76% of UC samples in the prospective MSK-IMPACT tumor sequencing cohort (N=1057); most frequent in KDM6A (31%), KMT2D (28%) and ARID1A (27%). Comparison of primary low-grade (N=65), high-grade (N=742) and meta...

Cancer Research

Genomic rearrangements leading to the aberrant expression of ERG are the most common early events... more Genomic rearrangements leading to the aberrant expression of ERG are the most common early events in prostate cancer and are significantly enriched for the concomitant loss of PTEN. Genetically engineered mouse models reveal that ERG overexpression alone is not sufficient to induce tumorigenesis, but combined loss of PTEN results in an aggressive invasive phenotype. Here we show that oncogenic ERG repressed PI3K signaling though direct transcriptional suppression of IRS2 leading to reduced RTK levels and activity. In accordance with this finding, ERG positive human prostate cancers had a repressed AKT gene signature and transcriptional down-regulation of IRS2. While overexpression of IRS2 activated PI3K signaling, promoting cell migration in a PI3K dependent manner, this did not fully recapitulate the phenotype seen with loss of PTEN as PI3K signaling is not as robust as observed in the setting of loss of PTEN. Importantly, deletions of the PTEN locus, which promotes active PI3K signaling, were among the most significant copy number alterations that co-occurred with ERG genomic rearrangements. This work provides insight on how initiating oncogenic events may directly influence the selection of secondary concomitant alterations to promote oncogenic signaling during tumor evolution. Significance This work provides insight on how initiating oncogenic events may directly influence the selection of secondary concomitant alterations to promote tumorigenesis.