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1.
Nat Commun ; 11(1): 2124, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358507

RESUMO

Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.

2.
Trends Genet ; 36(5): 318-336, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32294413

RESUMO

Quantitative trait loci (QTL) analysis is an important approach to investigate the effects of genetic variants identified through an increasing number of large-scale, multidimensional 'omics data sets. In this 'big data' era, the research community has identified a significant number of molecular QTLs (molQTLs) and increased our understanding of their effects. Herein, we review multiple categories of molQTLs, including those associated with transcriptome, post-transcriptional regulation, epigenetics, proteomics, metabolomics, and the microbiome. We summarize approaches to identify molQTLs and to infer their causal effects. We further discuss the integrative analysis of molQTLs through a multi-omics perspective. Our review highlights future opportunities to better understand the functional significance of genetic variants and to utilize the discovery of molQTLs in precision medicine.

3.
Nat Commun ; 11(1): 1779, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286310

RESUMO

Immune checkpoint blockade therapies have extended patient survival across multiple cancer lineages, but there is a heated debate on whether cancer immunotherapy efficacy is different between male and female patients. We summarize the existing meta-analysis to show inconsistent conclusions for whether gender is associated with the immunotherapy response. We analyze molecular profiling from ICB-treated patients to identify molecular differences for immunotherapy responsiveness. We perform comprehensive analyses for patients from The Cancer Genome Atlas (TCGA) and reveal divergent patterns for sex bias in immune features across multiple cancer types. We further validate our observations in multiple independent data sets. Considering that the majority of clinical trials are in melanoma and lung cancer, meta-analyses that pool multiple cancer types have limitations to discern whether cancer immunotherapy efficacy is different between male and female patients. Future studies should include omics profiling to investigate sex-associated molecular differences in immunotherapy.

5.
Cancer Cell ; 37(3): 324-339.e8, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32183950

RESUMO

Here, we show that tumor ADORA1 deletion suppresses cell growth in human melanoma cell lines in vitro and tumor development in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PD-L1 levels, which inactivates cocultured T cells in vitro, compromises anti-tumor immunity in vivo, and reduces anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of ADORA1-deficient or ADORA1 antagonist-treated melanoma and NSCLC immune-competent mouse models. Mechanistically, we identify ATF3 as the factor transcriptionally upregulating PD-L1 expression. Tumor ATF3 deletion improves the effect of ADORA1 antagonist treatment of melanoma and NSCLC xenografts. We observe higher ADORA1, lower ATF3, and lower PD-L1 expression levels in tumor tissues from nonresponders among PD-1 mAb-treated NSCLC patients.

7.
Nat Genet ; 52(3): 342-352, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32024997

RESUMO

Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.


Assuntos
Variações do Número de Cópias de DNA , Genoma Humano/genética , Genoma Mitocondrial/genética , Neoplasias/genética , Sequenciamento Completo do Genoma , Ciclo Celular/genética , Reparo do DNA/genética , DNA Mitocondrial/genética , Humanos , Mutação , Fosforilação Oxidativa , Análise de Sequência de RNA
8.
Nat Cell Biol ; 22(1): 108-119, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31915373

RESUMO

Owing to the prevalence and high mortality rates of cardiac diseases, a more detailed characterization of the human heart is necessary; however, this has been largely impeded by the cellular diversity of cardiac tissue and limited access to samples. Here, we show transcriptome profiling of 21,422 single cells-including cardiomyocytes (CMs) and non-CMs (NCMs)-from normal, failed and partially recovered (left ventricular assist device treatment) adult human hearts. Comparative analysis of atrial and ventricular cells revealed pronounced inter- and intracompartmental CM heterogeneity as well as compartment-specific utilization of NCM cell types as major cell-communication hubs. Systematic analysis of cellular compositions and cell-cell interaction networks showed that CM contractility and metabolism are the most prominent aspects that are correlated with changes in heart function. We also uncovered active engagement of NCMs in regulating the behaviour of CMs, exemplified by ACKR1+-endothelial cells, injection of which preserved cardiac function after injury. Beyond serving as a rich resource, our study provides insights into cell-type-targeted intervention of heart diseases.


Assuntos
Células Endoteliais/metabolismo , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Miócitos Cardíacos/metabolismo , Diferenciação Celular/fisiologia , Perfilação da Expressão Gênica/métodos , Humanos
9.
Autophagy ; : 1-15, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31920150

RESUMO

KRAS is the most frequently mutated oncogene in human neoplasia. Despite a large investment to understand the effects of KRAS mutation in cancer cells, the direct effects of the oncogenetic KRAS activation on immune cells remain elusive. Here, we report that extracellular KRASG12D is essential for pancreatic tumor-associated macrophage polarization. Oxidative stress induces KRASG12D protein release from cancer cells succumbing to autophagy-dependent ferroptosis. Extracellular KRASG12D packaged into exosomes then is taken up by macrophages through an AGER-dependent mechanism. KRASG12D causes macrophages to switch to an M2-like pro-tumor phenotype via STAT3-dependent fatty acid oxidation. Consequently, the disruption of KRASG12D release and uptake can abolish the macrophage-mediated stimulation of pancreatic adenocarcinomas in mouse models. Importantly, the level of KRASG12D expression in macrophages correlates with poor survival in pancreatic cancer patients. These findings not only identify extracellular KRASG12D as a key mediator of cancer cell-macrophage communication, but also provide a novel KRAS-targeted anticancer strategy.Abbreviations: DAMP, damage-associated molecular pattern; PBMCMs, peripheral blood mononuclear cell-derived macrophages; PDAC, pancreatic ductal adenocarcinoma; s.c., subcutaneously; TAMs, tumor-associated macrophages; TME, tumor microenvironment.

10.
Nucleic Acids Res ; 48(D1): D34-D39, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31586392

RESUMO

Alternative polyadenylation (APA) is an RNA-processing mechanism on the 3' terminus that generates distinct isoforms of mRNAs and/or other RNA polymerase II transcripts with different 3'UTR lengths. Widespread APA affects post-transcriptional gene regulation in mRNA translation, stability, and localization, and exhibits strong tissue specificity. However, no existing database provides comprehensive information about APA events in a large number of human normal tissues. Using the RNA-seq data from the Genotype-Tissue Expression project, we systematically identified APA events from 9475 samples across 53 human tissues and examined their associations with multiple traits and gene expression across tissues. We further developed APAatlas, a user-friendly database (https://hanlab.uth.edu/apa/) for searching, browsing and downloading related information. APAatlas will help the biomedical research community elucidate the functions and mechanisms of APA events in human tissues.

11.
G3 (Bethesda) ; 10(1): 189-198, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31712257

RESUMO

The relationship of genotypes to phenotypes can be modified by environmental inputs. Such crucial environmental inputs include metabolic cues derived from microbes living together with animals. Thus, the analysis of genetic effects on animals' physiology can be confounded by variations in the metabolic profile of microbes. Caenorhabditis elegans exposed to distinct bacterial strains and species exhibit phenotypes different at cellular, developmental, and behavioral levels. Here we reported metabolomic profiles of three Escherichia coli strains, B strain OP50, K-12 strain MG1655, and B-K-12 hybrid strain HB101, as well as different mitochondrial and fat storage phenotypes of C. elegans exposed to MG1655 and HB101 vs. OP50. We found that these metabolic phenotypes of C. elegans are not correlated with overall metabolic patterning of bacterial strains, but their specific metabolites. In particular, the fat storage phenotype is traced to the betaine level in different bacterial strains. HT115 is another K-12 E. coli strain that is commonly utilized to elicit an RNA interference response, and we showed that C. elegans exposed to OP50 and HT115 exhibit differences in mitochondrial morphology and fat storage levels. We thus generated an RNA interference competent OP50 (iOP50) strain that can robustly and consistently knockdown endogenous C. elegans genes in different tissues. Together, these studies suggest the importance of specific bacterial metabolites in regulating the host's physiology and provide a tool to prevent confounding effects when analyzing genotype-phenotype interactions under different bacterial backgrounds.

12.
Trends Mol Med ; 26(2): 135-137, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31836419

RESUMO

Spliceosomes comprise small nuclear (sn)RNAs and proteins. Through genome-wide analyses in large-scale tumor samples, recent studies by Shuai et al., Suzuki et al., and Inoue et al. have identified recurrent spliceosomal mutations that induced genome-wide splicing alterations of cancer-related genes to promote malignancy. These discoveries suggest novel RNA-based therapeutics in anticancer treatment.

13.
Methods Mol Biol ; 2082: 189-199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31849016

RESUMO

Expression quantitative trait loci (eQTL) analysis links variations in gene expression levels to genotypes. Analyzing both cis- and trans-eQTLs from tumor samples can provide an intermediate phenotype between genetic variation and complex traits to better understand how risk alleles contribute to tumorigenesis and development. Here we describe a detailed workflow for identifying eQTLs in cancer using existing packages and software. The key package is Matrix eQTL, which requires input data of genotypes, genes expression, and covariates. This pipeline can be easily applied in a related research field.

14.
J Exp Med ; 217(2)2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31757866

RESUMO

Systemic sclerosis (SSc; scleroderma) is a multisystem fibrotic disease. The mammalian cleavage factor I 25-kD subunit (CFIm25; encoded by NUDT21) is a key regulator of alternative polyadenylation, and its depletion causes predominantly 3'UTR shortening through loss of stimulation of distal polyadenylation sites. A shortened 3'UTR will often lack microRNA target sites, resulting in increased mRNA translation due to evasion of microRNA-mediated repression. Herein, we report that CFlm25 is downregulated in SSc skin, primary dermal fibroblasts, and two murine models of dermal fibrosis. Knockdown of CFIm25 in normal skin fibroblasts is sufficient to promote the 3'UTR shortening of key TGFß-regulated fibrotic genes and enhance their protein expression. Moreover, several of these fibrotic transcripts show 3'UTR shortening in SSc skin. Finally, mice with CFIm25 deletion in fibroblasts show exaggerated skin fibrosis upon bleomycin treatment, and CFIm25 restoration attenuates bleomycin-induced skin fibrosis. Overall, our data link this novel RNA-processing mechanism to dermal fibrosis and SSc pathogenesis.

15.
Heliyon ; 5(10): e02739, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31720476

RESUMO

Objectives: The goal of this study was to prepare lyophilized platelet-rich fibrin (L-PRF) and analyze the combined use of L-PRF and osteogenic bone marrow mesenchymal stem cell (BMSC) sheet fragments for bone tissue engineering via in vivo injection. Methods: First, fresh PRF (F-PRF) was lyophilized to prepare L-PRF, the characteristics of which were examined through gross morphological, and histological and microstructural observations. In addition, the kinetics of growth factor release from L-PRF and F-PRF were also determined by enzyme-linked immunosorbent assay (ELISA). Subsequently, after assessing the proliferation and osteogenic differentiation of BMSCs exposed to L-PRF or F-PRF in vitro, we subcutaneously injected BMSC sheet fragments with L-PRF or F-PRF into nude mice and assessed bone formation through microcomputed tomography and histological analyses. Results: We observed that L-PRF released growth factors that favored BMSC proliferation and osteogenic differentiation in vitro. The combined use of L-PRF and osteogenic BMSC sheet fragments enabled bone tissue regeneration in vivo, and no significant difference between the F-PRF and L-PRF groups was observed (P = 0.24). Conclusions: The results of this study demonstrate that the combined use of L-PRF and osteogenic BMSC sheets may have potential in the fabrication of engineered bone.

16.
BMC Biol ; 17(1): 89, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722692

RESUMO

BACKGROUND: Cardiac differentiation from human pluripotent stem cells provides a unique opportunity to study human heart development in vitro and offers a potential cell source for cardiac regeneration. Compared to the large body of studies investigating cardiac maturation and cardiomyocyte subtype-specific induction, molecular events underlying cardiac lineage commitment from pluripotent stem cells at early stage remain poorly characterized. RESULTS: In order to uncover key molecular events and regulators controlling cardiac lineage commitment from a pluripotent state during differentiation, we performed single-cell RNA-Seq sequencing and obtained high-quality data for 6879 cells collected from 6 stages during cardiac differentiation from human embryonic stem cells and identified multiple cell subpopulations with distinct molecular features. Through constructing developmental trajectory of cardiac differentiation and putative ligand-receptor interactions, we revealed crosstalk between cardiac progenitor cells and endoderm cells, which could potentially provide a cellular microenvironment supporting cardiac lineage commitment at day 5. In addition, computational analyses of single-cell RNA-Seq data unveiled ETS1 (ETS Proto-Oncogene 1) activation as an important downstream event induced by crosstalk between cardiac progenitor cells and endoderm cells. Consistent with the findings from single-cell analysis, chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) against ETS1 revealed genomic occupancy of ETS1 at cardiac structural genes at day 9 and day 14, whereas ETS1 depletion dramatically compromised cardiac differentiation. CONCLUSION: Together, our study not only characterized the molecular features of different cell types and identified ETS1 as a crucial factor induced by cell-cell crosstalk contributing to cardiac lineage commitment from a pluripotent state, but may also have important implications for understanding human heart development at early embryonic stage, as well as directed manipulation of cardiac differentiation in regenerative medicine.

17.
Artif Cells Nanomed Biotechnol ; 47(1): 4012-4019, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31591910

RESUMO

Gold nanoparticles (AuNPs) as the most excellent anticancer theranostic nanoparticles were synthesized through efficient, simple, and green synthesis method using Marsdenia tenacissima plant extracts and they are widely characterized by several techniques including ultraviolet-visible (UV) spectroscopy, atomic force microscopy (AFM), energy-dispersive X-ray spectrometers (EDS), transmission electron microscopy (TEM), and Fourier transform infrared (FT-IR) spectroscopy. From the AuNPs synthesized by M. tenacissima extracts, it was discovered that particle size around 50 nm, which is admirable nano dimension, was achieved by plant-mediated synthesis. After characterization of these nanoparticles, they performed as in vitro anticancer activity against lung cancer cell lines (A549). MTT assay revealed that AuNPs produce toxicity based on the dose-dependent A549 cells growth inhibition. AuNPs treatment activates caspase expression and down-regulates the anti-apoptotic protein expression in A549 cells. Our results point out that the AuNPs from M. tenacissima extract are apposite stabilizing agents, which serve as an effective anticancer agent against lung cancer cell lines (A549).


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ouro/química , Marsdenia/química , Nanopartículas Metálicas/química , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/genética , Proliferação de Células/efeitos dos fármacos , Ouro/farmacologia , Química Verde , Humanos , Neoplasias Pulmonares/patologia , Tamanho da Partícula , Extratos Vegetais/química , Extratos Vegetais/farmacologia
18.
Nat Commun ; 10(1): 4562, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594934

RESUMO

Enhancer RNA (eRNA) is a type of noncoding RNA transcribed from the enhancer. Although critical roles of eRNA in gene transcription control have been increasingly realized, the systemic landscape and potential function of eRNAs in cancer remains largely unexplored. Here, we report the integration of multi-omics and pharmacogenomics data across large-scale patient samples and cancer cell lines. We observe a cancer-/lineage-specificity of eRNAs, which may be largely driven by tissue-specific TFs. eRNAs are involved in multiple cancer signaling pathways through putatively regulating their target genes, including clinically actionable genes and immune checkpoints. They may also affect drug response by within-pathway or cross-pathway means. We characterize the oncogenic potential and therapeutic liability of one eRNA, NET1e, supporting the clinical feasibility of eRNA-targeted therapy. We identify a panel of clinically relevant eRNAs and developed a user-friendly data portal. Our study reveals the transcriptional landscape and clinical utility of eRNAs in cancer.


Assuntos
Antineoplásicos/farmacologia , Elementos Facilitadores Genéticos/genética , Neoplasias/terapia , RNA não Traduzido/antagonistas & inibidores , Transcrição Genética/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Ensaios de Seleção de Medicamentos Antitumorais , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Genômica , Humanos , Concentração Inibidora 50 , Terapia de Alvo Molecular/métodos , Neoplasias/genética , Proteínas Oncogênicas/genética , Regiões Promotoras Genéticas , RNA não Traduzido/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
J Clin Invest ; 129(12): 5261-5277, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31503548

RESUMO

Beclin 1 (Becn1) is a key molecule in the autophagy pathway and has been implicated in cancer development. Due to the embryonic lethality of homozygous Becn1-deficient mice, the precise mechanisms and cell type-specific roles of Becn1 in regulating inflammation and cancer immunity remain elusive. Here, we report that myeloid-deficient Becn1 (Becn1ΔM) mice developed neutrophilia, were hypersusceptible to LPS-induced septic shock, and had a high risk of developing spontaneous precursor B cell (pre-B cell) lymphoma with elevated expression of immunosuppressive molecules programmed death ligand 1 (PD-L1) and IL-10. Becn1 deficiency resulted in the stabilization of MEKK3 and aberrant p38 activation in neutrophils, and mediated neutrophil-B cell interaction through Cxcl9/Cxcr3 chemotaxis. Neutrophil-B cell interplay further led to the activation of IL-21/STAT3/IRF1 and CD40L/ERK signaling and PD-L1 expression; therefore, it suppressed CD8+ T cell function. Ablation of p38 in Becn1ΔM mice prevented neutrophil inflammation and B cell tumorigenesis. Importantly, the low expression of Becn1 in human neutrophils was significantly correlated with the PD-L1 levels in pre-B acute lymphoblastic lymphoma (ALL) patients. Our findings have identified myeloid Becn1 as a key regulator of cancer immunity and therapeutic target for pre-B cell lymphomas.

20.
PeerJ ; 7: e7644, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534863

RESUMO

Perna viridis and P. canaliculus are economically and ecologically important species of shellfish. In this study, the complete ribosomal DNA (rDNA) unit sequences of these species were determined for the first time. The gene order, 18S rRNA-internal transcribed spacer (ITS) 1-5.8S rRNA-ITS2-28S rRNA-intergenic spacer (IGS), was similar to that observed in other eukaryotes. The lengths of the P. viridis and P. canaliculus rDNA sequences ranged from 8,432 to 8,616 bp and from 7,597 to 7,610 bp, respectively, this variability was mainly attributable to the IGS region. The putative transcription termination site and initiation site were confirmed. Perna viridis and P. canaliculus rDNA contained two (length: 93 and 40 bp) and one (length: 131 bp) repeat motifs, respectively. Individual intra-species differences mainly involved the copy number of repeat units. In P. viridis, three cytosine-guanine (CpG) sites with sizes of 440, 1,075 and 537 bp were found to cover nearly the entire IGS sequence, whereas in P. canaliculus, two CpG islands with sizes of 361 and 484 bp were identified. The phylogenetic trees constructed with maximum likelihood and neighbour-joining methods and based on ITS sequences were identical and included three major clusters. Species of the same genus were easily clustered together.

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