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Yao Y, Yang X, Fu Y, Zhang Y. Immunological features of various molecular subtypes of cervical cancer and their prognostic implications in the context of disulfidptosis. Front Oncol 2025; 15:1574911. [PMID: 40438679 PMCID: PMC12116334 DOI: 10.3389/fonc.2025.1574911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 04/25/2025] [Indexed: 06/01/2025] Open
Abstract
Objective Cervical cancer ranks among the most prevalent malignancies impacting women globally. Disulfidptosis represents a recently identified pathway of cellular demise, although its role in the context of cervical cancer is not well elucidated. This research investigates the significance of Disulfidptosis-Related Genes (DRGs) within cervical cancer. Furthermore, it aims to analyze the differences in prognosis and immune infiltration among different molecular subtypes. Methods We compiled genes associated with cervical cancer and disulfidptosis from a variety of databases to perform a differential expression analysis. Subsequently, the samples are grouped through consensus clustering. To evaluate immune cell infiltration, we employed CIBERSORT. Additionally, immune checkpoint genes (ICGs) were gathered from existing literature and databases, enabling statistical analyses of two subtype samples of cervical cancer (CESC). Following our analyses using GO, KEGG, and GSEA to compare the differences between the two subtypes. Lastly, a prognostic risk model was constructed using LASSO regression and validated using ROC. Results This study identified seven key genes: PCBP3, ARNT, ANP32E, DSTN, CD2AP, EPAS1, and ACTN1.The consensus clustering analysis showed differences in immune cell infiltration and DFS(disease-free survival) among the various clusters. The immune checkpoint gene CXCL1 displayed highly significant statistical differences between subtype A (Cluster 1) and subtype B (Cluster 2) in cervical cancer (CESC) samples. The gene set enrichment analysis identified the negative regulation of peptidase activity and the IL-17 signaling pathway, which link to subtype-specific differentially expressed genes (DEGs). Conclusion Statistical analysis of the various subtypes of CESC samples highlighted the importance of subtype-specific therapeutic targets. Additionally, it seeks to enhance the accuracy of prognostic predictions, thereby establishing a foundation for the formulation of personalized treatment approaches.
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Affiliation(s)
- Yadan Yao
- Department of Gynecology, Jiaxing University Affiliated Traditional Chinese Medicine (TCM) Hospital, Jiaxing, Zhejiang, China
| | - Xiaomin Yang
- Department of Gynecology, Jiaxing University Affiliated Traditional Chinese Medicine (TCM) Hospital, Jiaxing, Zhejiang, China
| | - Yuanxin Fu
- Department of Acupuncture and Massage, Jiaxing University Affiliated Traditional Chinese Medicine (TCM) Hospital, Jiaxing, Zhejiang, China
| | - Yinmin Zhang
- Department of Pediatrics, Jiaxing University Affiliated Traditional Chinese Medicine (TCM) Hospital, Jiaxing, Zhejiang, China
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Torres MB, Leung CH, Zoghbi M, Lazcano R, Ingram D, Wani K, Keung EZ, Zarzour MA, Scally CP, Hunt KK, Conley A, Bishop AJ, Guadagnolo BA, Farooqi A, Mitra D, Yoder AK, Nakazawa MS, Araujo D, Livingston A, Ratan R, Patel S, Ravi V, Lazar AJ, Roland CL, Somaiah N, Nassif Haddad EF. Dedifferentiated liposarcomas treated with immune checkpoint blockade: the MD Anderson experience. Front Immunol 2025; 16:1567736. [PMID: 40370451 PMCID: PMC12075363 DOI: 10.3389/fimmu.2025.1567736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 04/11/2025] [Indexed: 05/16/2025] Open
Abstract
Background Dedifferentiated liposarcoma (DDLPS) is one of the most common types of soft tissue sarcoma (STS) characterized by liposarcomatous differentiation and a predilection for the retroperitoneum. Despite the growing number of histology-specific immune checkpoint blockade (ICB) trials in STS, it is still difficult to identify the radiographic objective response rate (ORR) for DDLPS in the real world setting. This study aimed to evaluate the ORR and survival of patients with DDLPS treated with ICB at a single center. Methods We conducted a retrospective study of 31 patients with pathologically confirmed DDLPS treated with ICB at MD Anderson Cancer Center between 2018 and 2023. Patient demographics, disease characteristics, treatment history, and response to ICB were analyzed. Immunohistochemical analysis was performed on tumor samples to assess immune-related markers. Results ORR by RECIST 1.1 was 3.2% (n=1/31). Among all patients (n=31), 6% achieved partial radiographic response, while 39% had stable disease, and 55% showed progressive disease. Median progression-free survival (PFS) was 3.5 (95%CI:1.9, 4.7) months, and overall survival (OS) after ICB initiation was 19.7 (95%CI: 8.8, not reached) months. Patients without prior systemic therapy demonstrated better OS (p=0.004). Immunohistochemistry revealed no relationship between pre- or post-ICB expression of CD8, CD20, CD21 and PDL-1 and response. Conclusion While the response to ICB in DDLPS remains limited, specific immune markers may influence treatment outcomes. CD20/21 post-ICB appear more important for prognosis. Further research is warranted to identify predictive factors for ICB efficacy in DDLPS.
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Affiliation(s)
- Madeline B. Torres
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Surgery, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ, United States
| | - Cheuk Hong Leung
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Marianne Zoghbi
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Rossana Lazcano
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Davis Ingram
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Khalida Wani
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Emily Z. Keung
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - M. Alejandra Zarzour
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Christopher P. Scally
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Kelly K. Hunt
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Anthony Conley
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Andrew J. Bishop
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - B. Ashleigh Guadagnolo
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ahsan Farooqi
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Devarati Mitra
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Alison K. Yoder
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Michael S. Nakazawa
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Dejka Araujo
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Andrew Livingston
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ravin Ratan
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Shreyaskumar Patel
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Vinod Ravi
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Alexander J. Lazar
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Christina L. Roland
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Neeta Somaiah
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elise F. Nassif Haddad
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Zhu N, Hou J, Zhang Y, Yang N, Ding K, Chang C, Liu Y, Gu H, Chen B, Wei X, Zhu L. A prognostic glycolysis-related gene signature in osteosarcoma: implications for metabolic programming, immune microenvironment, and drug response. PeerJ 2025; 13:e19369. [PMID: 40321814 PMCID: PMC12047218 DOI: 10.7717/peerj.19369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 04/04/2025] [Indexed: 05/08/2025] Open
Abstract
Background/Aims Osteosarcoma (OS), a malignant tumor originating in the bone or cartilage, primarily affects children and adolescents. Notably, glycolysis is the main target for metabolic programming to ensuring the energy supply for cancer. This study aimed to establish a glycolysis-related gene (GRG) risk signature in OS to comprehensively assessing the pathogenic, prognosis, and their application in predicting drug response. Methods mRNA expression profiles were acquired from the Gene Expression Omnibus (GEO, GSE16091, GSE39058, and GSE21257). Using the non-negative matrix factorization (NMF) algorithm, patients with OS were stratified into distinct subgroups based on 288 GRGs identified through univariable Cox analysis. Univariate Cox regression analysis of differentially expressed genes (DEGs) between the molecular clusters was conducted to establish a risk signature comprising GRGs in OS. The prognostic efficacy of this risk signature was assessed via Kaplan-Meier curve analysis and Cox regression, evaluating its independence as a prognostic indicator. Additionally, the predictive potential of the risk model for drug response was evaluated using the "OncoPredict" package. Furthermore, the distribution of immune cell types in single-cell RNA sequencing (scRNA-seq) data was examined in correlation with the four identified GRGs risk signatures, followed by validation of expression levels in vitro using RT-PCR. Results Patients diagnosed with OS were categorized into two distinct molecular subgroups, exhibiting notable variations in prognosis and tumor microenvironment. Univaria te Cox regression analysis was employed to identify four GRGs, namely chondroitin sulfate glucuronyltransferase (CHPF), Ras-related GTP-binding protein D (RRAGD), nucleoprotein TPR (TPR), and versican core protein (VCAN), which constitute a prognostic signature for patients with OS. This signature demonstrated robust prognostic value, as corroborated by Kaplan-Meier, univariate, and multivariate Cox regression analyses. Significant differences in tumor microenvironment immune infiltration (such as B cells, monocytes) were observed between molecular subgroups. Moreover, a significant disparity in drug sensitivity to AZD8055, paclitaxel, and PD0325901 was noted between the high-risk and low-risk cohorts, and the established four-gene risk signature served as dependable prognostic indicators in the validation cohort, confirmed at the cellular level through external dataset validation and reverse transcription quantitative PCR (RT-qPCR) experiments. Conclusion A risk signature based on GRGs was established for OS, exhibiting robust predictive efficacy for prognostic assessment, and offering significant clinical utility for the prognosis of OS.
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Affiliation(s)
- Naiqiang Zhu
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jingyi Hou
- Hebei Province Key Laboratory of Study and Exploitation of Chinese Medicine, Chengde Medical University, Chengde, China
| | - Yu Zhang
- Hebei Key Laboratory of Panvascular Diseases, Chengde, China
| | - Ning Yang
- Hebei Key Laboratory of Panvascular Diseases, Chengde, China
| | - KaiKai Ding
- Hebei Key Laboratory of Panvascular Diseases, Chengde, China
| | - Chengbing Chang
- Department of Minimally Invasive Spinal Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Yanqi Liu
- Hebei Key Laboratory of Panvascular Diseases, Chengde, China
| | - Haipeng Gu
- Hebei Key Laboratory of Panvascular Diseases, Chengde, China
| | - Bin Chen
- Department of Minimally Invasive Spinal Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Xu Wei
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Liguo Zhu
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Rahmati R, Zarimeidani F, Ahmadi F, Yousefi-Koma H, Mohammadnia A, Hajimoradi M, Shafaghi S, Nazari E. Identification of novel diagnostic and prognostic microRNAs in sarcoma on TCGA dataset: bioinformatics and machine learning approach. Sci Rep 2025; 15:7521. [PMID: 40032929 PMCID: PMC11876432 DOI: 10.1038/s41598-025-91007-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 02/17/2025] [Indexed: 03/05/2025] Open
Abstract
The discovery of unique microRNA (miR) patterns and their corresponding genes in sarcoma patients indicates their involvement in cancer development and suggests their potential use in medical management. MiRs were identified from The Cancer Genome Atlas (TCGA) dataset, with a Deep Neural Network (DNN) employed for novel miR identification. MiRDB facilitated target predictions. Functional enrichment analysis, identify critical pathways, protein-protein interaction network, and diseases/clinical data correlations were explored. COX regression, Kaplan-Meier analyses, and CombioROC was also utilized. The population consisted of 119 females and 142 males, and 1046 miRs were uncovered. Ten miRs was selected for further analysis using DNN. Upon analyzing for gene ontology, it was found that these genes showed enrichment in various activities. We identified a significant association between the overall survival rate of sarcoma patients and miRs levels. The combination of miR.3688 and miR.3936 achieved the greatest diagnostic standing. MiRs have the capability to screen sarcoma patients to identify undetected tumors, predict prognosis, and pinpoint prospective targets for treatment. Further large clinical trials are required to validate our findings.
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Affiliation(s)
- Rahem Rahmati
- Students Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
- Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Zarimeidani
- Students Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
- Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farnaz Ahmadi
- Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hannaneh Yousefi-Koma
- Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdolreza Mohammadnia
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Hajimoradi
- Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shadi Shafaghi
- Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Elham Nazari
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Li R, Yao F, Liu Y, Wu X, Su P, Li T, Wu N. Mining TCGA to reveal immunotherapy-related genes for soft tissue sarcoma. Medicine (Baltimore) 2025; 104:e41392. [PMID: 40020124 PMCID: PMC11875607 DOI: 10.1097/md.0000000000041392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 08/02/2024] [Indexed: 03/05/2025] Open
Abstract
Immunotherapy of soft tissue sarcoma is considered an important development direction for the future. Bioinformatics analysis of genetic changes in tumors and the immune microenvironment around tumors has proven to be a mature and reliable method for predicting tumor prognosis. By mining the Cancer Genome Atlas Program database, we found immunotherapy targets of soft tissue sarcoma and analyzed their biological behavior. The data of 265 samples were downloaded to analyze the expression profile of soft tissue sarcomas. This included calculating tumor purity through the estimation of stromal and immune cells in malignant tumors using expression data, acquisition of differential genes as prognostic factors, and enrichment analysis of the differential genes. Survival analysis showed longer overall survival times for patients with higher immune scores. We obtained 83 survival-related differential genes through survival analysis, and 23 genes that could be used as independent risk factors for the prognosis of soft tissue sarcoma were obtained by multiple regression analysis of the differential genes and other recognized risk factors. Gene set enrichment analysis of the differential genes obtained immune and inflammatory gene ontology terms and signal pathways, including regulation of the T-cell apoptotic process and leukocyte transendothelial migration. After validation in an independent data set of the Gene Expression Omnibus database, 12 genes were confirmed as a result. We believe that these differential genes will be new targets for sarcoma immunotherapy and key genes for the prognosis of soft tissue sarcoma.
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Affiliation(s)
- Ruixin Li
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Fan Yao
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Yijin Liu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Xiaodan Wu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Peng Su
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Tianran Li
- Department of Radiology, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Nan Wu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, China
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Yang J, Cali Daylan AE, Shevkoplias A, Postovalova E, Wang M, Tyshevich A, Lee M, Narvel H, Zornikova K, Shin N, Kotlov N, Paoluzzi L, Zhu C, Halmos B, Zang X, Cheng H. Transcriptomic Profiling and Tumor Microenvironment Classification Reveal Unique and Dynamic Immune Biology in HIV-Associated Kaposi Sarcoma. Cells 2025; 14:134. [PMID: 39851562 PMCID: PMC11764145 DOI: 10.3390/cells14020134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 01/06/2025] [Accepted: 01/14/2025] [Indexed: 01/26/2025] Open
Abstract
Kaposi Sarcoma (KS) is a vascular tumor originating from endothelial cells and is associated with human herpesvirus 8 (KSHV) infection. It disproportionately affects populations facing health disparities. Although antiretroviral therapy (ART) has improved KS control in people with HIV (PWH), treatment options for advanced KS remain limited. This study investigates the tumor microenvironment (TME) of KS through whole-transcriptomic profiling, analyzing changes over time and differences based on HIV status. The TME was categorized into four subtypes: immune-enriched (IE), non-fibrotic, immune-enriched/fibrotic (IE/F), fibrotic (F) and immune-depleted (D). Nine KS patients (four HIV-negative and five HIV-positive) were enrolled in the study. Longitudinally collected KS samples from three patients (one HIV-negative and two HIV-positive) allowed for the investigation of dynamic TME changes within individual patients. The immune cellular composition was determined using deconvolution and compared to a cohort of non-KS patients. Our findings revealed that all KS samples, regardless of HIV status, were enriched in endothelial cells. Compared to non-KS tissues, the KS samples contained a higher percentage of NK and CD8+ T cells. HIV-negative KS samples displayed the IE and IE/F TME subtypes, while HIV-positive samples exhibited IE, IE/F, and F subtypes. Over the course of the disease, a decrease in angiogenic signatures was observed in two HIV-positive KS patients. Notably, HIV-negative KS samples showed alterations in NK cell-mediated immunity and cytotoxic response pathways, whereas HIV-positive samples exhibited changes in growth regulation and protein kinase activity pathways at the time of initial diagnosis. The gene expression of immune checkpoints, including CD274 (PD-L1) and PDCD1LC2 (PD-L2), was comparable between HIV-positive and HIV-negative KS samples at diagnosis. Furthermore, sequencing identified a shared TCRβ chain in all patients analyzed, indicating a T-cell immune response to a common antigen. This study demonstrates unique transcriptomic features and TME subtypes in KS that differ based on HIV status. Additionally, it illustrates longitudinal dynamic changes in the gene signatures and TME subtypes in individual patients. The identification of a shared TCRβ chain suggests that immune T cells in KS patients may target a common antigen. Future studies should further explore the immune microenvironment and unique T cell clonotypes, which could pave the way for the development of novel therapeutic strategies for KS patients.
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Affiliation(s)
- Jihua Yang
- Department of Oncology (Medical Oncology), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (J.Y.); (A.E.C.D.); (M.W.); (M.L.); (B.H.); (X.Z.)
| | - Ayse Ece Cali Daylan
- Department of Oncology (Medical Oncology), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (J.Y.); (A.E.C.D.); (M.W.); (M.L.); (B.H.); (X.Z.)
| | - Aleksei Shevkoplias
- Research and Development, BostonGene Corporation, Waltham, MA 02453, USA; (A.S.); (E.P.); (K.Z.); (N.K.)
| | - Ekaterina Postovalova
- Research and Development, BostonGene Corporation, Waltham, MA 02453, USA; (A.S.); (E.P.); (K.Z.); (N.K.)
| | - Meng Wang
- Department of Oncology (Medical Oncology), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (J.Y.); (A.E.C.D.); (M.W.); (M.L.); (B.H.); (X.Z.)
| | - Andrey Tyshevich
- Research and Development, BostonGene Corporation, Waltham, MA 02453, USA; (A.S.); (E.P.); (K.Z.); (N.K.)
| | - Matthew Lee
- Department of Oncology (Medical Oncology), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (J.Y.); (A.E.C.D.); (M.W.); (M.L.); (B.H.); (X.Z.)
| | - Hiba Narvel
- Department of Medicine, Jacobi Medical Center, Bronx, NY 10461, USA;
| | - Ksenia Zornikova
- Research and Development, BostonGene Corporation, Waltham, MA 02453, USA; (A.S.); (E.P.); (K.Z.); (N.K.)
| | - Nara Shin
- Research and Development, BostonGene Corporation, Waltham, MA 02453, USA; (A.S.); (E.P.); (K.Z.); (N.K.)
| | - Nikita Kotlov
- Research and Development, BostonGene Corporation, Waltham, MA 02453, USA; (A.S.); (E.P.); (K.Z.); (N.K.)
| | - Luca Paoluzzi
- Clinical Sciences, Oncology, Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA;
| | - Changcheng Zhu
- Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
| | - Balazs Halmos
- Department of Oncology (Medical Oncology), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (J.Y.); (A.E.C.D.); (M.W.); (M.L.); (B.H.); (X.Z.)
| | - Xingxing Zang
- Department of Oncology (Medical Oncology), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (J.Y.); (A.E.C.D.); (M.W.); (M.L.); (B.H.); (X.Z.)
| | - Haiying Cheng
- Department of Oncology (Medical Oncology), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (J.Y.); (A.E.C.D.); (M.W.); (M.L.); (B.H.); (X.Z.)
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Nie G, Liu C, Tian Z. Comprehensive analysis of prognostic and immunological role of basement membrane-related genes in soft tissue sarcoma. Immun Inflamm Dis 2024; 12:e70037. [PMID: 39392257 PMCID: PMC11467964 DOI: 10.1002/iid3.70037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 09/18/2024] [Accepted: 09/30/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND Soft tissue sarcoma (STS) represents highly multifarious malignant tumors that often occur in adolescents and have a poor prognosis. The basement membrane, as an ancient cellular matrix, was recently proven to play a vital role in developing abundant tumors. The relationship between basement membrane-related genes and STS remains unknown. METHODS Consensus clustering was employed to identify subgroups related to differentially expressed basement membrane-related genes. Cox and least absolute shrinkage and selection operator regression analyses were utilized to construct this novel signature. Then, we established a nomogram and calibration curve, including the risk score and available clinical characteristics. Finally, we carried out functional enrichment analysis and immune microenvironment analysis to investigate enriched pathways and the tumor immune microenvironment related to the novel signature. RESULTS A prognostic predictive signature consisting of eight basement membrane-related genes was established. Kaplan-Meier survival curves demonstrated that the patients in the high-risk group had a poor prognosis. Independent analysis illustrated that this risk model could be an independent prognostic predictor. We validated the accuracy of our signature in the validation data set. In addition, gene set enrichment analysis and immune microenvironment analysis showed that patients with low-risk scores were enriched in some pathways associated with immunity. Finally, in vitro experiments showed significantly differential expression levels of these signature genes in STS cells and PSAT1 could promote the malignant behavior of STS. CONCLUSIONS The novel signature is a promising prognostic predictor for STS. The present study may improve the prognosis and enhance individualized treatment for STS in the future.
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Affiliation(s)
- Guang‐hua Nie
- Department of Foot and Ankle Surgery, Honghui HospitalXi'an Jiaotong UniversityXi'anChina
| | - Cheng‐yi Liu
- Department of Foot and Ankle Surgery, Honghui HospitalXi'an Jiaotong UniversityXi'anChina
| | - Zhao Tian
- Department of Hand Surgery, Honghui HospitalXi'an Jiaotong UniversityXi'anChina
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Liu Q, Zhu J, Huang Z, Zhang X, Yang J. Identification of Novel Cuproptosis-Related Genes Mediating the Prognosis and Immune Microenvironment in Cholangiocarcinoma. Technol Cancer Res Treat 2024; 23:15330338241239139. [PMID: 38613350 PMCID: PMC11015765 DOI: 10.1177/15330338241239139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/30/2024] [Accepted: 02/26/2024] [Indexed: 04/14/2024] Open
Abstract
BACKGROUND Cuproptosis is a novel type of mediated cell death strongly associated with the progression of several cancers and has been implicated as a potential therapeutic target. However, the role of cuproptosis in cholangiocarcinoma for prognostic prediction, subgroup classification, and therapeutic strategies remains largely unknown. METHODS A systematic analysis was conducted among 146 cuproptosis-related genes and clinical information based on independent mRNA and protein datasets to elucidate the potential mechanisms and prognostic prediction value of cuproptosis-related genes. A 10-cuproptosis-related gene prediction model was constructed, and its effects on cholangiocarcinoma prognosis were significantly connected to poor patient survival. Additionally, the expression patterns of our model included genes that were validated with several cholangiocarcinoma cancer cell lines and a normal biliary epithelial cell line. RESULTS First, a 10-cuproptosis-related gene signature (ADAM9, ADAM17, ALB, AQP1, CDK1, MT2A, PAM, SOD3, STEAP3, and TMPRSS6) displayed excellent predictive performance for the overall survival of cholangiocarcinoma. The low-cuproptosis group had a significantly better prognosis than the high-cuproptosis group with transcriptome and protein cohorts. Second, compared with the high-risk and low-risk groups, the 2 groups displayed distinct tumor microenvironments, reduced proportions of endothelial cells, and increased levels of cancer-associated fibroblasts based on CIBERSORTx and EPIC analyses. Third, patients' sensitivities to chemotherapeutic drugs and immune checkpoints revealed distinctive differences between the 2 groups. Finally, in replicating the expression patterns of the 10 genes, these results were validated with quantitative real-time polymerase chain reaction results validating the abnormal expression pattern of the target genes in cholangiocarcinoma. CONCLUSIONS Collectively, we established and verified an effective prognostic model that could separate cholangiocarcinoma patients into 2 heterogeneous cuproptosis subtypes based on the molecular or protein characteristics of 10 cuproptosis-related genes. These findings may provide potential benefits for unveiling molecular characteristics and defining subgroups could improve the early diagnosis and individualized treatment of cholangiocarcinoma patients.
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Affiliation(s)
- Qiang Liu
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Jianpeng Zhu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhicheng Huang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaofeng Zhang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou, China
- Hangzhou Institute of Digestive Diseases, Hangzhou, China
| | - Jianfeng Yang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou, China
- Hangzhou Institute of Digestive Diseases, Hangzhou, China
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9
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Jumaniyazova E, Lokhonina A, Dzhalilova D, Kosyreva A, Fatkhudinov T. Immune Cells in the Tumor Microenvironment of Soft Tissue Sarcomas. Cancers (Basel) 2023; 15:5760. [PMID: 38136307 PMCID: PMC10741982 DOI: 10.3390/cancers15245760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/04/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Soft tissue sarcomas (STSs) are a rare heterogeneous group of malignant neoplasms characterized by their aggressive course and poor response to treatment. This determines the relevance of research aimed at studying the pathogenesis of STSs. By now, it is known that STSs is characterized by complex relationships between the tumor cells and immune cells of the microenvironment. Dynamic interactions between tumor cells and components of the microenvironment enhance adaptation to changing environmental conditions, which provides the high aggressive potential of STSs and resistance to antitumor therapy. Today, active research is being conducted to find effective antitumor drugs and to evaluate the possibility of using therapy with immune cells of STS. The difficulty in assessing the efficacy of new antitumor options is primarily due to the high heterogeneity of this group of malignant neoplasms. Studying the role of immune cells in the microenvironment in the progression STSs and resistance to antitumor therapies will provide the discovery of new biomarkers of the disease and the prediction of response to immunotherapy. In addition, it will help to initially divide patients into subgroups of good and poor response to immunotherapy, thus avoiding wasting precious time in selecting the appropriate antitumor agent.
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Affiliation(s)
- Enar Jumaniyazova
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia (T.F.)
| | - Anastasiya Lokhonina
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia (T.F.)
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997 Moscow, Russia
| | - Dzhuliia Dzhalilova
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia (T.F.)
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Anna Kosyreva
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia (T.F.)
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Timur Fatkhudinov
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia (T.F.)
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
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10
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Liu Y, Liang Y, Su Y, Hu J, Sun J, Zheng M, Huang Z. Exploring the potential mechanisms of Yi-Yi-Fu-Zi-Bai-Jiang-San therapy on the immune-inflamed phenotype of colorectal cancer via combined network pharmacology and bioinformatics analyses. Comput Biol Med 2023; 166:107432. [PMID: 37729701 DOI: 10.1016/j.compbiomed.2023.107432] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 07/16/2023] [Accepted: 08/28/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND The development and progression of colorectal cancer (CRC) is closely associated with its complex tumor microenvironment (TME). Assessment of the modified pattern of immune cell infiltration (ICI) will help increase knowledge regarding the characteristics of TME infiltration. Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS) has been shown to have positive effects on the regulation of the immune microenvironment of CRC. However, its pharmacological targets and molecular mechanisms remain to be elucidated. METHODS Network pharmacological analysis was used to identify the target of YYFZBJS in the TME of CRC. Patients with the immune-inflamed phenotype (IIP) were identified using CRC samples from The Cancer Genome Atlas (TCGA) database. Consensus genes were identified by intersecting YYFZBJS targets, CRC disease targets and differentially expressed genes in the CRC microenvironment. Then, least absolute shrinkage and selection operator (LASSO) Cox analyses were used to identify a prognostic signature from the consensus genes. Cytoscape software was further used to build a unique herb-compound-target network diagram of the important components of YYFZBJS and prognostic gene targets. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed using the prognostic gene sets to explore the molecular mechanism of the prognostic genes in drug therapy for CRC IIP patients. Finally, single-cell analysis was performed to validate the expression of the prognostic genes in the TME of CRC using the TISCH2 database. RESULTS A total of 284 IIP patients were identified from 480 patients with CRC. A total of 35 consensus genes were identified as targets of YYFZBJS in the TME of CRC patients. An eleven-gene prognostic signature, including PIK3CG, C5AR1, PRF1, CAV1, HPGDS, PTGS2, SERPINE1, IDO1, TGFB1, CXCR2 and MMP9, was identified from the consensus genes, with areas under the receiver operating characteristic (ROC) curve (AUCs) values of 0.84 and 0.793 for the training and test cohorts, respectively. In the herb-compound-target network, twenty-four compounds were shown to interact with the 11 prognostic genes, which were significantly enriched in the IL-17 signaling, arachidonic acid metabolism and metabolic pathways. Single-cell analysis of the prognostic genes confirmed that their abnormal expression was associated with the TME of CRC. CONCLUSION This study organically integrated network pharmacology and bioinformatics analyses to identify prognostic genes in CRC IIP patients from the targets of YYFZBJS. Although this data mining work was limited to the study of mechanisms related to prognosis based on the immune microenvironment, the methodology provides new perspectives in the search for novel therapeutic targets of traditional Chinese medicines (TCMs) and accurate diagnostic indicators of cancers targeted by TCMs.
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Affiliation(s)
- Yong Liu
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, Guangdong, PR China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, 523808, Guangdong, PR China
| | - Youcheng Liang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, PR China
| | - Yongjian Su
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, Guangdong, PR China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, 523808, Guangdong, PR China
| | - Jiaqi Hu
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, Guangdong, PR China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, 523808, Guangdong, PR China
| | - Jianbo Sun
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, Guangdong, PR China
| | - Mingbin Zheng
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, Guangdong, PR China; National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518112, Guangdong, PR China.
| | - Zunnan Huang
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, Guangdong, PR China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, 523808, Guangdong, PR China; Marine Medical Research Institute of Guangdong Zhanjiang, Zhanjiang, 524023, Guangdong, PR China.
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11
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Beird HC, Wu CC, Nakazawa M, Ingram D, Daniele JR, Lazcano R, Little L, Davies C, Daw NC, Wani K, Wang WL, Song X, Gumbs C, Zhang J, Rubin B, Conley A, Flanagan AM, Lazar AJ, Futreal PA. Complete loss of TP53 and RB1 is associated with complex genome and low immune infiltrate in pleomorphic rhabdomyosarcoma. HGG ADVANCES 2023; 4:100224. [PMID: 37593416 PMCID: PMC10428123 DOI: 10.1016/j.xhgg.2023.100224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 07/14/2023] [Indexed: 08/19/2023] Open
Abstract
Rhabdomyosarcoma accounts for roughly 1% of adult sarcomas, with pleomorphic rhabdomyosarcoma (PRMS) as the most common subtype. Survival outcomes remain poor for patients with PRMS, and little is known about the molecular drivers of this disease. To better characterize PRMS, we performed a broad array of genomic and immunostaining analyses on 25 patient samples. In terms of gene expression and methylation, PRMS clustered more closely with other complex karyotype sarcomas than with pediatric alveolar and embryonal rhabdomyosarcoma. Immune infiltrate levels in PRMS were among the highest observed in multiple sarcoma types and contrasted with low levels in other rhabdomyosarcoma subtypes. Lower immune infiltrate was associated with complete loss of both TP53 and RB1. This comprehensive characterization of the genetic, epigenetic, and immune landscape of PRMS provides a roadmap for improved prognostications and therapeutic exploration.
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Affiliation(s)
- Hannah C. Beird
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Chia-Chin Wu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael Nakazawa
- Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Davis Ingram
- Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Joseph R. Daniele
- TRACTION Platform, Division of Therapeutics Discovery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rossana Lazcano
- Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Latasha Little
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Christopher Davies
- Research Department of Pathology, UCL Cancer Institute, London WC1E 6DD, UK
| | - Najat C. Daw
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Khalida Wani
- Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Wei-Lien Wang
- Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xingzhi Song
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Curtis Gumbs
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Brian Rubin
- Institute Chair, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Anthony Conley
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Adrienne M. Flanagan
- Research Department of Pathology, UCL Cancer Institute, London WC1E 6DD, UK
- Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK
| | - Alexander J. Lazar
- Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - P. Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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12
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Leng D, Yang Z, Sun H, Song C, Huang C, Ip KU, Chen G, Deng CX, Zhang XD, Zhao Q. Comprehensive Analysis of Tumor Microenvironment Reveals Prognostic ceRNA Network Related to Immune Infiltration in Sarcoma. Clin Cancer Res 2023; 29:3986-4001. [PMID: 37527025 PMCID: PMC10543973 DOI: 10.1158/1078-0432.ccr-22-3396] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 06/23/2023] [Accepted: 07/28/2023] [Indexed: 08/03/2023]
Abstract
PURPOSE Sarcoma is the second most common solid tumor type in children and adolescents. The high level of tumor heterogeneity as well as aggressive behavior of sarcomas brings serious difficulties to developing effective therapeutic strategies for clinical application. Therefore, it is of great importance to identify accurate biomarkers for early detection and prognostic prediction of sarcomas. EXPERIMENTAL DESIGN In this study, we characterized three subtypes of sarcomas based on tumor immune infiltration levels (TIIL), and constructed a prognosis-related competing endogenous RNA (ceRNA) network to investigate molecular regulations in the sarcoma tumor microenvironment (TME). We further built a subnetwork consisting of mRNAs and lncRNAs that are targets of key miRNAs and strongly correlated with each other in the ceRNA network. After validation using public data and experiments in vivo and in vitro, we deeply dug the biological role of the miRNAs and lncRNAs in a subnetwork and their impact on TME. RESULTS Altogether, 5 miRNAs (hsa-mir-125b-2, hsa-mir-135a-1, hsa-mir92a-2, hsa-mir-181a-2, and hsa-mir-214), 3 lncRNAs (LINC00641, LINC01146, and LINC00892), and 10 mRNAs (AGO2, CXCL10, CD86, CASP1, IKZF1, CD27, CD247, CD69, CCR2, and CSF2RB) in the subnetwork were identified as vital regulators to shape the TME. On the basis of the systematic network, we identified that trichostatin A, a pan-HDAC inhibitor, could potentially regulate the TME of sarcoma, thereby inhibiting the tumor growth. CONCLUSIONS Our study identifies a ceRNA network as a promising biomarker for sarcoma. This system provides a more comprehensive understanding and a novel perspective of how ceRNAs are involved in shaping sarcoma TME.
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Affiliation(s)
- Dongliang Leng
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau
| | - Ziyi Yang
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau
| | - Heng Sun
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China
| | - Chengcheng Song
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau
- Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Chen Huang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, SAR, China
- Stat Key laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, SAR, China
| | - Ka U. Ip
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau
| | - Guokai Chen
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China
- Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China
- Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Chu-Xia Deng
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China
- Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Xiaohua Douglas Zhang
- Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, Kentucky
| | - Qi Zhao
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China
- Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, SAR, China
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13
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Ye H, Lu M, Tu C, Min L. Necroptosis in the sarcoma immune microenvironment: From biology to therapy. Int Immunopharmacol 2023; 122:110603. [PMID: 37467689 DOI: 10.1016/j.intimp.2023.110603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 06/23/2023] [Accepted: 07/02/2023] [Indexed: 07/21/2023]
Abstract
Apoptosis resistance remains a major obstacle to treatment failure in sarcoma. Necroptosis is a caspase-independent programmed cell death, investigated as a novel strategy to eradicate anti-apoptotic tumor cells. The process is mediated by the receptor-interacting proteins kinase family and mixed lineage kinase domain-like proteins, which is morphologically similar to necrosis. Recent studies suggest that necroptosis in the tumor microenvironment has pro- or anti-tumor effects on immune response and cancer development. Necroptosis-related molecules display a remarkable value in prognosis prediction and therapeutic response evaluation of sarcoma. Furthermore, the induction of tumor necroptosis has been explored as a feasible therapeutic strategy against sarcoma and to synergize with immunotherapy. This review discusses the dual roles of necroptosis in the immune microenvironment and tumor progression, and explores the potential of necroptosis as a new target for sarcoma treatment.
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Affiliation(s)
- Huali Ye
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Minxun Lu
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Chongqi Tu
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Li Min
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China.
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14
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Puttock EH, Tyler EJ, Manni M, Maniati E, Butterworth C, Burger Ramos M, Peerani E, Hirani P, Gauthier V, Liu Y, Maniscalco G, Rajeeve V, Cutillas P, Trevisan C, Pozzobon M, Lockley M, Rastrick J, Läubli H, White A, Pearce OMT. Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis. Nat Commun 2023; 14:2514. [PMID: 37188691 PMCID: PMC10185550 DOI: 10.1038/s41467-023-38093-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
Recent studies have shown that the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and responsiveness to immunotherapy. A question that remains unresolved is whether the ECM directly educates the immune phenotypes seen in tumors. Here, we identify a tumor-associated macrophage (TAM) population associated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether the ECM was capable of generating this TAM phenotype, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissue. ECM-educated macrophages have a tissue-remodeling and immunoregulatory phenotype, inducing altered T cell marker expression and proliferation. We conclude that the tumor ECM directly educates this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.
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Affiliation(s)
- E H Puttock
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - E J Tyler
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - M Manni
- Department of Biomedicine and Division of Medical Oncology, University Hospital Basel, Hebelstrasse 20, 4031, Basel, Switzerland
| | - E Maniati
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - C Butterworth
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - M Burger Ramos
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - E Peerani
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - P Hirani
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - V Gauthier
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - Y Liu
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - G Maniscalco
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - V Rajeeve
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - P Cutillas
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - C Trevisan
- Department of Women and Children Health, University of Padova and Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Corso Stati Uniti 4, 35127, Padova, Italy
| | - M Pozzobon
- Department of Women and Children Health, University of Padova and Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Corso Stati Uniti 4, 35127, Padova, Italy
| | - M Lockley
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK
| | - J Rastrick
- UCB Pharma Ltd, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK
| | - H Läubli
- Department of Biomedicine and Division of Medical Oncology, University Hospital Basel, Hebelstrasse 20, 4031, Basel, Switzerland
| | - A White
- UCB Pharma Ltd, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK
| | - O M T Pearce
- Queen Mary University of London, Barts Cancer Institute, John Vane Science Centre, London, EC1M 6BQ, UK.
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15
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Li L, Yang W, Jia D, Zheng S, Gao Y, Wang G. Establishment of a N1-methyladenosine-related risk signature for breast carcinoma by bioinformatics analysis and experimental validation. Breast Cancer 2023:10.1007/s12282-023-01458-1. [PMID: 37178414 DOI: 10.1007/s12282-023-01458-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 04/09/2023] [Indexed: 05/15/2023]
Abstract
OBJECTIVES Breast carcinoma (BRCA) has resulted in a huge health burden globally. N1-methyladenosine (m1A) RNA methylation has been proven to play key roles in tumorigenesis. Nevertheless, the function of m1A RNA methylation-related genes in BRCA is indistinct. METHODS The RNA sequencing (RNA-seq), copy-number variation (CNV), single-nucleotide variant (SNV), and clinical data of BRCA were acquired via The Cancer Genome Atlas (TCGA) database. In addition, the GSE20685 dataset, the external validation set, was acquired from the Gene Expression Omnibus (GEO) database. 10 m1A RNA methylation regulators were obtained from the previous literature, and further analyzed through differential expression analysis by rank-sum test, mutation by SNV data, and mutual correlation by Pearson Correlation Analysis. Furthermore, the differentially expressed m1A-related genes were selected through overlapping m1A-related module genes obtained by weighted gene co-expression network analysis (WGCNA), differentially expressed genes (DEGs) in BRCA and DEGs between high- and low- m1A score subgroups. The m1A-related model genes in the risk signature were derived by univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. In addition, a nomogram was built through univariate and multivariate Cox analyses. After that, the immune infiltration between the high- and low-risk groups was investigated through ESTIMATE and CIBERSORT. Finally, the expression trends of model genes in clinical BRCA samples were further confirmed by quantitative real-time PCR (RT‒qPCR). RESULTS Eighty-five differentially expressed m1A-related genes were obtained. Among them, six genes were selected as prognostic biomarkers to build the risk model. The validation results of the risk model showed that its prediction was reliable. In addition, Cox independent prognosis analysis revealed that age, risk score, and stage were independent prognostic factors for BRCA. Moreover, 13 types of immune cells were different between the high- and low-risk groups and the immune checkpoint molecules TIGIT, IDO1, LAG3, ICOS, PDCD1LG2, PDCD1, CD27, and CD274 were significantly different between the two risk groups. Ultimately, RT-qPCR results confirmed that the model genes MEOX1, COL17A1, FREM1, TNN, and SLIT3 were significantly up-regulated in BRCA tissues versus normal tissues. CONCLUSIONS An m1A RNA methylation regulator-related prognostic model was constructed, and a nomogram based on the prognostic model was constructed to provide a theoretical reference for individual counseling and clinical preventive intervention in BRCA.
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Affiliation(s)
- Leilei Li
- Department of Pathology, Kunming Medical University, Kunming, Yunnan, 650500, People's Republic of China
| | - Wenhui Yang
- Department of Digestive Oncology, Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030032, People's Republic of China
| | - Daqi Jia
- Department of Pathology, Kunming Medical University, Kunming, Yunnan, 650500, People's Republic of China
| | - Shiqi Zheng
- Department of Pathology, Kunming Medical University, Kunming, Yunnan, 650500, People's Republic of China
| | - Yuzhe Gao
- Department of Breast Surgery, Guizhou Provincial People's Hospital, Guiyang, Guizhou, 550002, People's Republic of China.
| | - Guanghui Wang
- Department of Breast Surgery, Guizhou Provincial People's Hospital, Guiyang, Guizhou, 550002, People's Republic of China.
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Li S, Chen X, Chen J, Wu B, Liu J, Guo Y, Li M, Pu X. Multi-omics integration analysis of GPCRs in pan-cancer to uncover inter-omics relationships and potential driver genes. Comput Biol Med 2023; 161:106988. [PMID: 37201441 DOI: 10.1016/j.compbiomed.2023.106988] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 03/30/2023] [Accepted: 04/27/2023] [Indexed: 05/20/2023]
Abstract
G protein-coupled receptors (GPCRs) are the largest drug target family. Unfortunately, applications of GPCRs in cancer therapy are scarce due to very limited knowledge regarding their correlations with cancers. Multi-omics data enables systematic investigations of GPCRs, yet their effective integration remains a challenge due to the complexity of the data. Here, we adopt two types of integration strategies, multi-staged and meta-dimensional approaches, to fully characterize somatic mutations, somatic copy number alterations (SCNAs), DNA methylations, and mRNA expressions of GPCRs in 33 cancers. Results from the multi-staged integration reveal that GPCR mutations cannot well predict expression dysregulation. The correlations between expressions and SCNAs are primarily positive, while correlations of the methylations with expressions and SCNAs are bimodal with negative correlations predominating. Based on these correlations, 32 and 144 potential cancer-related GPCRs driven by aberrant SCNA and methylation are identified, respectively. In addition, the meta-dimensional integration analysis is carried out by using deep learning models, which predict more than one hundred GPCRs as potential oncogenes. When comparing results between the two integration strategies, 165 cancer-related GPCRs are common in both, suggesting that they should be prioritized in future studies. However, 172 GPCRs emerge in only one, indicating that the two integration strategies should be considered concurrently to complement the information missed by the other such that obtain a more comprehensive understanding. Finally, correlation analysis further reveals that GPCRs, in particular for the class A and adhesion receptors, are generally immune-related. In a whole, the work is for the first time to reveal the associations between different omics layers and highlight the necessity of combing the two strategies in identifying cancer-related GPCRs.
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Affiliation(s)
- Shiqi Li
- College of Chemistry, Sichuan University, Chengdu, 610064, China.
| | - Xin Chen
- College of Chemistry, Sichuan University, Chengdu, 610064, China.
| | - Jianfang Chen
- College of Chemistry, Sichuan University, Chengdu, 610064, China.
| | - Binjian Wu
- College of Chemistry, Sichuan University, Chengdu, 610064, China.
| | - Jing Liu
- College of Chemistry, Sichuan University, Chengdu, 610064, China.
| | - Yanzhi Guo
- College of Chemistry, Sichuan University, Chengdu, 610064, China.
| | - Menglong Li
- College of Chemistry, Sichuan University, Chengdu, 610064, China.
| | - Xuemei Pu
- College of Chemistry, Sichuan University, Chengdu, 610064, China.
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Chen J, Lian Y, Zhao B, Han J, Li X, Wu J, Hou M, Yue M, Zhang K, Liu G, Tu M, Ruan W, Ji S, An Y. Deciphering the Prognostic and Therapeutic Significance of Cell Cycle Regulator CENPF: A Potential Biomarker of Prognosis and Immune Microenvironment for Patients with Liposarcoma. Int J Mol Sci 2023; 24:ijms24087010. [PMID: 37108172 PMCID: PMC10139200 DOI: 10.3390/ijms24087010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/30/2023] [Accepted: 03/30/2023] [Indexed: 04/29/2023] Open
Abstract
Liposarcoma (LPS) is one of the most common subtypes of sarcoma with a high recurrence rate. CENPF is a regulator of cell cycle, differential expression of which has been shown to be related with various cancers. However, the prognostic value of CENPF in LPS has not been deciphered yet. Using data from TCGA and GEO datasets, the expression difference of CENPF and its effects on the prognosis or immune infiltration of LPS patients were analyzed. As results show, CENPF was significantly upregulated in LPS compared to normal tissues. Survival curves illustrated that high CENPF expression was significantly associated with adverse prognosis. Univariate and multivariate analysis suggested that CENPF expression could be an independent risk factor for LPS. CENPF was closely related to chromosome segregation, microtubule binding and cell cycle. Immune infiltration analysis elucidated a negative correlation between CENPF expression and immune score. In conclusion, CENPF not only could be considered as a potential prognostic biomarker but also a potential malignant indicator of immune infiltration-related survival for LPS. The elevated expression of CENPF reveals an unfavorable prognostic outcome and worse immune score. Thus, therapeutically targeting CENPF combined with immunotherapy might be an attractive strategy for the treatment of LPS.
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Affiliation(s)
- Jiahao Chen
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Yingying Lian
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Binbin Zhao
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Jiayang Han
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Xinyu Li
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Jialin Wu
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Mengwen Hou
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Man Yue
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Kaifeng Zhang
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Guangchao Liu
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Mengjie Tu
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Weimin Ruan
- Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng 475004, China
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Shaoping Ji
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
| | - Yang An
- Cell Signal Transduction Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Bioinformatics Center, Henan University, Kaifeng 475004, China
- Kaifeng Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng 475004, China
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Gutierrez WR, Scherer A, Rytlewski JD, Laverty EA, Sheehan AP, McGivney GR, Brockman QR, Knepper-Adrian V, Roughton GA, Quelle DE, Gordon DJ, Monga V, Dodd RD. Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism. JCI Insight 2022; 7:e159419. [PMID: 36227698 PMCID: PMC9746804 DOI: 10.1172/jci.insight.159419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 10/11/2022] [Indexed: 12/15/2022] Open
Abstract
The DNA methyltransferase inhibitor decitabine has classically been used to reactivate silenced genes and as a pretreatment for anticancer therapies. In a variation of this idea, this study explores the concept of adding low-dose decitabine (DAC) following administration of chemotherapy to bolster therapeutic efficacy. We find that addition of DAC following treatment with the chemotherapy agent gemcitabine improves survival and slows tumor growth in a mouse model of high-grade sarcoma. Unlike prior studies in epithelial tumor models, DAC did not induce a robust antitumor T cell response in sarcoma. Furthermore, DAC synergizes with gemcitabine independently of the immune system. Mechanistic analyses demonstrate that the combination therapy induces biphasic cell cycle arrest and apoptosis. Therapeutic efficacy was sequence dependent, with gemcitabine priming cells for treatment with DAC through inhibition of ribonucleotide reductase. This study identifies an apparently unique application of DAC to augment the cytotoxic effects of conventional chemotherapy in an immune-independent manner. The concepts explored in this study represent a promising paradigm for cancer treatment by augmenting chemotherapy through addition of DAC to increase tolerability and improve patient response. These findings have widespread implications for the treatment of sarcomas and other aggressive malignancies.
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Affiliation(s)
- Wade R. Gutierrez
- Cancer Biology Graduate Program
- Medical Scientist Training Program
- Holden Comprehensive Cancer Center
- Department of Internal Medicine
| | - Amanda Scherer
- Holden Comprehensive Cancer Center
- Department of Internal Medicine
| | | | | | - Alexa P. Sheehan
- Holden Comprehensive Cancer Center
- Department of Internal Medicine
- Molecular Medicine Graduate Program
| | - Gavin R. McGivney
- Cancer Biology Graduate Program
- Holden Comprehensive Cancer Center
- Department of Internal Medicine
- Department of Molecular Physiology and Biophysics
| | - Qierra R. Brockman
- Holden Comprehensive Cancer Center
- Department of Internal Medicine
- Molecular Medicine Graduate Program
| | | | | | - Dawn E. Quelle
- Cancer Biology Graduate Program
- Medical Scientist Training Program
- Holden Comprehensive Cancer Center
- Molecular Medicine Graduate Program
- Department of Neuroscience and Pharmacology
- Department of Pathology, and
| | - David J. Gordon
- Holden Comprehensive Cancer Center
- Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA
| | - Varun Monga
- Holden Comprehensive Cancer Center
- Department of Internal Medicine
| | - Rebecca D. Dodd
- Cancer Biology Graduate Program
- Medical Scientist Training Program
- Holden Comprehensive Cancer Center
- Department of Internal Medicine
- Molecular Medicine Graduate Program
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19
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Lazcano R, Barreto CM, Salazar R, Carapeto F, Traweek RS, Leung CH, Gite S, Mehta J, Ingram DR, Wani KM, Vu KAT, Parra ER, Lu W, Zhou J, Witt RG, Cope B, Thirasastr P, Lin HY, Scally CP, Conley AP, Ratan R, Livingston JA, Zarzour AM, Ludwig J, Araujo D, Ravi V, Patel S, Benjamin R, Wargo J, Wistuba II, Somaiah N, Roland CL, Keung EZ, Solis L, Wang WL, Lazar AJ, Nassif EF. The immune landscape of undifferentiated pleomorphic sarcoma. Front Oncol 2022; 12:1008484. [PMID: 36313661 PMCID: PMC9597628 DOI: 10.3389/fonc.2022.1008484] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/19/2022] [Indexed: 11/25/2022] Open
Abstract
Introduction Undifferentiated pleomorphic sarcoma (UPS) can be associated with a relatively dense immune infiltration. Immune checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are effective in 20% of UPS patients. We characterize the immune microenvironment of UPS and its association with oncologic outcomes. Material and methods Surgically resected UPS samples were stained by immunohistochemistry (IHC) for the following: tumor-associated immune cells (CD3, CD8, CD163, CD20), immune checkpoints (stimulatory: OX40, ICOS; inhibitory: PD-L1, LAG3, IDO1, PD1), and the adenosine pathway (CD73, CD39). Sections were reviewed for the presence of lymphoid aggregates (LA). Clinical data were retrospectively obtained for all samples. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to compare distributions. Correlations between biomarkers were measured by Spearman correlation. Univariate and multivariate Cox models were used to identify biomarkers associated with overall survival (OS) and disease-free survival (DFS). Unsupervised clustering was performed, and Kaplan-Meier curves and log-rank tests used for comparison of OS and DFS between immune clusters. Results Samples analyzed (n=105) included 46 primary tumors, 34 local recurrences, and 25 metastases. LA were found in 23% (n=10/43), 17% (n=4/24), and 30% (n=7/23) of primary, recurrent, and metastatic samples, respectively. In primary UPS, CD73 expression was significantly higher after preoperative radiation therapy (p=0.009). CD39 expression was significantly correlated with PD1 expression (primary: p=0.002, recurrent: p=0.004, metastatic: p=0.001), PD-L1 expression (primary: p=0.009), and CD3+ cell densities (primary: p=0.016, recurrent: p=0.043, metastatic: p=0.028). In recurrent tumors, there was a strong correlation between CD39 and CD73 (p=0.015), and both were also correlated with CD163+ cell densities (CD39 p=0.013; CD73 p<0.001). In multivariate analyses, higher densities of CD3+ and CD8+ cells (Cox Hazard Ratio [HR]=0.33; p=0.010) were independently associated with OS (CD3+, HR=0.19, p<0.001; CD8+, HR= 0.33, p=0.010) and DFS (CD3+, HR=0.34, p=0.018; CD8+, HR=0.34, p= 0.014). Unsupervised clustering of IHC values revealed three immunologically distinct clusters: immune high, intermediate, and low. In primary tumors, these clusters were significantly associated with OS (log-rank p<0.0001) and DFS (p<0.001). Conclusion We identified three immunologically distinct clusters of UPS Associated with OS and DFS. Our data support further investigations of combination anti-PD-1/PD-L1 and adenosine pathway inhibitors in UPS.
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Affiliation(s)
- Rossana Lazcano
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Carmelia M. Barreto
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ruth Salazar
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Fernando Carapeto
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Raymond S. Traweek
- Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Cheuk H. Leung
- Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Swati Gite
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jay Mehta
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Davis R. Ingram
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Khalida M. Wani
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Kim-Anh T. Vu
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Edwin R. Parra
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Wei Lu
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jianling Zhou
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Russell G. Witt
- Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Brandon Cope
- Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Prapassorn Thirasastr
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Heather Y. Lin
- Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Christopher P. Scally
- Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Anthony P. Conley
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ravin Ratan
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - J. Andrew Livingston
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Alexandra M. Zarzour
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Joseph Ludwig
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Dejka Araujo
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Vinod Ravi
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Shreyaskumar Patel
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Robert Benjamin
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jennifer Wargo
- Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ignacio I. Wistuba
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States
| | - Neeta Somaiah
- Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Christina L. Roland
- Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Emily Z. Keung
- Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Luisa Solis
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Wei-Lien Wang
- Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States
| | - Alexander J. Lazar
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Division of Pathology and Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States
- Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elise F. Nassif
- Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- *Correspondence: Elise F. Nassif,
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Li H, Lin D, Wang X, Feng Z, Zhang J, Wang K. The development of a novel signature based on the m6A RNA methylation regulator-related ceRNA network to predict prognosis and therapy response in sarcomas. Front Genet 2022; 13:894080. [PMID: 36313417 PMCID: PMC9597465 DOI: 10.3389/fgene.2022.894080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
Background: N6 methyladenosine (m6A)-related noncoding RNAs (including lncRNAs and miRNAs) are closely related to the development of cancer. However, the gene signature and prognostic value of m6A regulators and m6A-associated RNAs in regulating sarcoma (SARC) development and progression remain largely unexplored. Therefore, further research is required. Methods: We obtained expression data for RNA sequencing (RNA-seq) and miRNAs of SARC from The Cancer Genome Atlas (TCGA) datasets. Correlation analysis and two target gene prediction databases (miRTarBase and LncBase v.2) were used to deduce m6A-related miRNAs and lncRNAs, and Cytoscape software was used to construct ceRNA-regulating networks. Based on univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses, an m6A-associated RNA risk signature (m6Ascore) model was established. Prognostic differences between subgroups were explored using Kaplan–Meier (KM) analysis. Risk score-related biological phenotypes were analyzed in terms of functional enrichment, tumor immune signature, and tumor mutation signature. Finally, potential immunotherapy features and drug sensitivity predictions for this model were also discussed. Results: A total of 16 miRNAs, 104 lncRNAs, and 11 mRNAs were incorporated into the ceRNA network. The risk score was obtained based on RP11-283I3.6, hsa-miR-455-3p, and CBLL1. Patients were divided into two risk groups using the risk score, with patients in the low-risk group having longer overall survival (OS) than those in the high-risk group. The receiver operating characteristic (ROC) curves indicated that risk characteristic performed well in predicting the prognosis of patients with SARC. In addition, lower m6Ascore was also positively correlated with the abundance of immune cells such as monocytes and mast cells activated, and several immune checkpoint genes were highly expressed in the low-m6Ascore group. According to our analysis, lower m6Ascore may lead to better immunotherapy response and OS outcomes. The risk signature was significantly associated with the chemosensitivity of SARC. Finally, a nomogram was constructed to predict the OS in patients with SARC. The concordance index (C-index) for the nomogram was 0.744 (95% CI: 0.707–0.784). The decision curve analysis (DCA), calibration plot, and ROC curve all showed that this nomogram had good predictive performance. Conclusion: This m6Ascore risk model based on m6A RNA methylation regulator-related RNAs may be promising for clinical prediction of prognosis and might contain potential biomarkers for treatment response prediction for SARC patients.
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Affiliation(s)
- Huling Li
- School of Public Health, Xinjiang Medical University, Urumqi, China
| | - Dandan Lin
- School of Public Health, Xinjiang Medical University, Urumqi, China
| | - Xiaoyan Wang
- School of Public Health, Xinjiang Medical University, Urumqi, China
| | - Zhiwei Feng
- School of Continuing Education, Xinjiang Medical University, Urumqi, China
| | - Jing Zhang
- School of Public Health, Xinjiang Medical University, Urumqi, China
| | - Kai Wang
- Department of Medical Engineering and Technology, Xinjiang Medical University, Urumqi, China
- *Correspondence: Kai Wang,
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Resag A, Toffanin G, Benešová I, Müller L, Potkrajcic V, Ozaniak A, Lischke R, Bartunkova J, Rosato A, Jöhrens K, Eckert F, Strizova Z, Schmitz M. The Immune Contexture of Liposarcoma and Its Clinical Implications. Cancers (Basel) 2022; 14:cancers14194578. [PMID: 36230502 PMCID: PMC9559230 DOI: 10.3390/cancers14194578] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022] Open
Abstract
Liposarcomas (LPS) are the most frequent malignancies in the soft tissue sarcoma family and consist of five distinctive histological subtypes, termed well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. They display variations in genetic alterations, clinical behavior, and prognostic course. While accumulating evidence implicates a crucial role of the tumor immune contexture in shaping the response to anticancer treatments, the immunological landscape of LPS is highly variable across different subtypes. Thus, DDLPS is characterized by a higher abundance of infiltrating T cells, yet the opposite was reported for MLPS. Interestingly, a recent study indicated that the frequency of pre-existing T cells in soft tissue sarcomas has a predictive value for immune checkpoint inhibitor (CPI) therapy. Additionally, B cells and tertiary lymphoid structures were identified as potential biomarkers for the clinical outcome of LPS patients and response to CPI therapy. Furthermore, it was demonstrated that macrophages, predominantly of M2 polarization, are frequently associated with poor prognosis. An improved understanding of the complex LPS immune contexture enables the design and refinement of novel immunotherapeutic approaches. Here, we summarize recent studies focusing on the clinicopathological, genetic, and immunological determinants of LPS.
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Affiliation(s)
- Antonia Resag
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Giulia Toffanin
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Gattamelata 64, 35128 Padova, Italy
| | - Iva Benešová
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany
- Department of Immunology, Second Faculty of Medicine, Charles University, University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech Republic
| | - Luise Müller
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Vlatko Potkrajcic
- Department of Radiation Oncology, Eberhard-Karls-University Tuebingen, Hoppe-Seyler-Straße 3, 72076 Tuebingen, Germany
| | - Andrej Ozaniak
- Third Department of Surgery, First Faculty of Medicine, Charles University, University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech Republic
| | - Robert Lischke
- Third Department of Surgery, First Faculty of Medicine, Charles University, University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech Republic
| | - Jirina Bartunkova
- Department of Immunology, Second Faculty of Medicine, Charles University, University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech Republic
| | - Antonio Rosato
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Gattamelata 64, 35128 Padova, Italy
- Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128 Padova, Italy
| | - Korinna Jöhrens
- Institute of Pathology, University Hospital Carl Gustav Carus, Fetscherstraße 74, 01307 Dresden, Germany
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Franziska Eckert
- Department of Radiation Oncology, Eberhard-Karls-University Tuebingen, Hoppe-Seyler-Straße 3, 72076 Tuebingen, Germany
- Department of Radiation Oncology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Zuzana Strizova
- Department of Immunology, Second Faculty of Medicine, Charles University, University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech Republic
- Correspondence: (Z.S.); (M.S.); Tel.: +420-604712471 (Z.S.); +49-351-458-6501 (M.S.)
| | - Marc Schmitz
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Correspondence: (Z.S.); (M.S.); Tel.: +420-604712471 (Z.S.); +49-351-458-6501 (M.S.)
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Liu B, Feng C, Liu Z, Tu C, Li Z. A novel necroptosis-related lncRNAs signature effectively predicts the prognosis for osteosarcoma and is associated with immunity. Front Pharmacol 2022; 13:944158. [PMID: 36105232 PMCID: PMC9465333 DOI: 10.3389/fphar.2022.944158] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 07/29/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Necroptosis is closely related to tumorigenesis and development. Accumulating evidence has revealed that long non-coding RNAs (lncRNAs) are also central players in osteosarcoma (OS). However, the role of necroptosis-related lncRNAs in OS remains unclear. In the present study, we aim to craft a prognostic signature based on necroptosis-related lncRNAs to improve the OS prognosis prediction. Methods: The signature based on necroptosis-related lncRNAs was discovered using univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis. The prognosis efficiency of the signature was then estimated by employing various bioinformatics methods. Subsequently, immunological analysis and Gene Set Enrichment Analysis (GSEA) were used to explore the association between necroptosis-related lncRNAs with clinical outcomes and immune status. More importantly, several necroptosis-related lncRNAs were validated with RT-qPCR. Results: Consequently, a novel prognosis signature was successfully constructed based on eight necroptosis-related lncRNAs. Meanwhile, the novel necroptosis-related lncRNAs model could distribute OS patients into two risk groups with a stable and accurate predictive ability. Additionally, the GSEA and immune analysis revealed that the necroptosis-related lncRNAs signature affects the development and prognosis of OS by regulating the immune status. The necroptosis-related lncRNA signature was closely correlated with multiple anticancer agent susceptibility. Moreover, the RT-qPCR results indicated several necroptosis-related lncRNAs were significantly differently expressed in osteosarcoma and osteoblast cell lines. Conclusion: In this summary, a novel prognostic signature integrating necroptosis-related lncRNAs was firstly constructed and could accurately predict the prognosis of OS. This study may increase the predicted value and guide the personalized chemotherapy treatment for OS.
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Affiliation(s)
- Binfeng Liu
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Chengyao Feng
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhongyue Liu
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Chao Tu
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- *Correspondence: Chao Tu, , Zhihong Li,
| | - Zhihong Li
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- *Correspondence: Chao Tu, , Zhihong Li,
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A novel anti-CD47-targeted blockade promotes immune activation in human soft tissue sarcoma but does not potentiate anti-PD-1 blockade. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04292-8. [DOI: 10.1007/s00432-022-04292-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 08/14/2022] [Indexed: 10/15/2022]
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Shi D, Mu S, Pu F, Zhong B, Hu B, Muhtar M, Tong W, Shao Z, Zhang Z, Liu J. Pan-sarcoma characterization of lncRNAs in the crosstalk of EMT and tumour immunity identifies distinct clinical outcomes and potential implications for immunotherapy. Cell Mol Life Sci 2022; 79:427. [PMID: 35842562 PMCID: PMC11071722 DOI: 10.1007/s00018-022-04462-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 06/16/2022] [Accepted: 07/01/2022] [Indexed: 11/29/2022]
Abstract
The epithelial-to-mesenchymal transition (EMT) is a reversible process that may interact with tumour immunity through multiple approaches. There is increasing evidence demonstrating the interconnections among EMT-related processes, the tumour microenvironment, and immune activity, as well as its potential influence on the immunotherapy response. Long non-coding RNAs (lncRNAs) are emerging as critical modulators of gene expression. They play fundamental roles in tumour immunity and act as promising biomarkers of immunotherapy response. However, the potential roles of lncRNA in the crosstalk of EMT and tumour immunity are still unclear in sarcoma. We obtained multi-omics profiling of 1440 pan-sarcoma patients from 19 datasets. Through an unsupervised consensus clustering approach, we categorised EMT molecular subtypes. We subsequently identified 26 EMT molecular subtype and tumour immune-related lncRNAs (EILncRNA) across pan-sarcoma types and developed an EILncRNA signature-based weighted scoring model (EILncSig). The EILncSig exhibited favourable performance in predicting the prognosis of sarcoma, and a high-EILncSig was associated with exclusive tumour microenvironment (TME) characteristics with desert-like infiltration of immune cells. Multiple altered pathways, somatically-mutated genes and recurrent CNV regions associated with EILncSig were identified. Notably, the EILncSig was associated with the efficacy of immune checkpoint inhibition (ICI) therapy. Using a computational drug-genomic approach, we identified compounds, such as Irinotecan that may have the potential to convert the EILncSig phenotype. By integrative analysis on multi-omics profiling, our findings provide a comprehensive resource for understanding the functional role of lncRNA-mediated immune regulation in sarcomas, which may advance the understanding of tumour immune response and the development of lncRNA-based immunotherapeutic strategies for sarcoma.
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Affiliation(s)
- Deyao Shi
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Shidai Mu
- Institute of Haematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Feifei Pu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Binlong Zhong
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Binwu Hu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Muradil Muhtar
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wei Tong
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhicai Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Jianxiang Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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25
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Liu B, Liu Z, Feng C, Tu C. A Necroptosis-Related lncRNA Signature Predicts Prognosis and Indicates the Immune Microenvironment in Soft Tissue Sarcomas. Front Genet 2022; 13:899545. [PMID: 35795204 PMCID: PMC9251335 DOI: 10.3389/fgene.2022.899545] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/30/2022] [Indexed: 11/24/2022] Open
Abstract
Background: The necroptosis and long noncoding RNA (lncRNA) are critical in the occurrence and development of malignancy, while the association between the necroptosis-related lncRNAs (NRlncRNAs) and soft tissue sarcoma (STS) remains controversial. Therefore, the present study aims to construct a novel signature based on NRlncRNAs to predict the prognosis of STS patients and investigate its possible role. Methods: The transcriptome data and clinical characteristics were extracted from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression database (GTEx). A novel NRlncRNA signature was established and verified by the COX regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis. Subsequently, the K-M survival analysis, ROC, univariate, multivariate Cox regression analysis, and nomogram were used to evaluate the predictive value of the signature. Also, a variety of bioinformatic analysis algorithms explored the differences between the potential mechanism, tumor immune status, and drug sensitivity in the two-risk group. Finally, the RT-qPCR was performed to evaluate the expression of signature NRlncRNAs. Results: A novel signature consisting of seven NRlncRNAs was successfully established and verified with stable prediction performance and general applicability for STS. Next, the GSEA showed that the patients in the high-risk group were mainly enriched with tumor-related pathways, while the low-risk patients were significantly involved in immune-related pathways. In parallel, we found that the STS patients in the low-risk group had a better immune status than that in the high-risk group. Additionally, there were significant differences in the sensitivity to anti-tumor agents between the two groups. Finally, the RT-qPCR results indicated that these signature NRlncRNAs were abnormally expressed in STS. Conclusion: To the best of our knowledge, it is the first study to construct an NRlncRNA signature for STS. More importantly, the novel signature displays stable value and translational potential for predicting prognosis, tumor immunogenicity, and therapeutic response in STS.
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Affiliation(s)
- Binfeng Liu
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhongyue Liu
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Chengyao Feng
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Chao Tu
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Chao Tu,
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Pan-Cancer Analyses of the Tumor Microenvironment Reveal That Ubiquitin-Conjugating Enzyme E2C Might Be a Potential Immunotherapy Target. J Immunol Res 2021; 2021:9250207. [PMID: 34950739 PMCID: PMC8689232 DOI: 10.1155/2021/9250207] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/28/2021] [Accepted: 11/15/2021] [Indexed: 11/18/2022] Open
Abstract
Increasing evidence indicated that the tumor microenvironment (TME) played a crucial role in cancer initiation and progression. Ubiquitin-conjugating enzyme E2C (UBE2C) was differentially expressed in many cancer types. However, the immunological and prognostic roles of UBE2C were unclear. Differentially expressed genes (DEGs) of 29 cancer types were downloaded from GEPIA2 and 4 cancer types failed to download owing to no DEGs. Furthermore, the gene expression profiles, mutation data, and survival data of 33 cancer types were obtained from UCSC Xena. Clinical stage relevance, tumor mutational burden (TMB), TME relevance analysis, and gene set enrichment analysis (GSEA) of DEGs in 33 cancer types were performed. And DEGs were identified in oral squamous cell carcinoma (OSCC) by biological experiments. Previous studies indicated that UBE2C was related to the prognosis of many cancers. In our study, the higher UBE2C expression level meant a terminal clinical stage in 8 cancer types and the expression level of UBE2C was related to TMB in 20 cancer types. In addition, both immune relevance analysis and GSEA showed that UBE2C might participate in immune response in many cancers. Furthermore, the UBE2C mRNA level and protein level were all identified as upregulated in OSCC cell lines and tissues. UBE2C was differentially expressed in many cancer types and related to the pathogenesis and TME of many cancers, which might be a potential diagnostic and therapeutic biomarker.
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Roulleaux Dugage M, Nassif EF, Italiano A, Bahleda R. Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review. Front Immunol 2021; 12:775761. [PMID: 34925348 PMCID: PMC8678134 DOI: 10.3389/fimmu.2021.775761] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/19/2021] [Indexed: 12/16/2022] Open
Abstract
Anti-PD-(L)1 therapies yield a disappointing response rate of 15% across soft-tissue sarcomas, even if some subtypes benefit more than others. The proportions of TAMs and TILs in their tumor microenvironment are variable, and this heterogeneity correlates to histotype. Tumors with a richer CD8+ T cell, M1 macrophage, and CD20+ cells infiltrate have a better prognosis than those infiltrated by M0/M2 macrophages and a high immune checkpoint protein expression. PD-L1 and CD8+ infiltrate seem correlated to response to immune checkpoint inhibitors (ICI), but tertiary lymphoid structures have the best predictive value and have been validated prospectively. Trials for combination therapies are ongoing and focus on the association of ICI with chemotherapy, achieving encouraging results especially with pembrolizumab and doxorubicin at an early stage, or ICI with antiangiogenics. A synergy with oncolytic viruses is seen and intratumoral talimogene laherpavec yields an impressive 35% ORR when associated to pembrolizumab. Adoptive cellular therapies are also of great interest in tumors with a high expression of cancer-testis antigens (CTA), such as synovial sarcomas or myxoid round cell liposarcomas with an ORR ranging from 20 to 50%. It seems crucial to adapt the design of clinical trials to histology. Leiomyosarcomas are characterized by complex genomics but are poorly infiltrated by immune cells and do not benefit from ICI. They should be tested with PIK3CA/AKT inhibition, IDO blockade, or treatments aiming at increasing antigenicity (radiotherapy, PARP inhibitors). DDLPS are more infiltrated and have higher PD-L1 expression, but responses to ICI remain variable across clinical studies. Combinations with MDM2 antagonists or CDK4/6 inhibitors may improve responses for DDLPS. UPS harbor the highest copy number alterations (CNA) and mutation rates, with a rich immune infiltrate containing TLS. They have a promising 15-40% ORR to ICI. Trials for ICB should focus on immune-high UPS. Association of ICI with FGFR inhibitors warrants further exploration in the immune-low group of UPS. Finally translocation-related sarcomas are heterogeneous, and although synovial sarcomas a poorly infiltrated and have a poor response rate to ICI, ASPS largely benefit from ICB monotherapy or its association with antiangiogenics agents. Targeting specific neoantigens through vaccine or adoptive cellular therapies is probably the most promising approach in synovial sarcomas.
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Affiliation(s)
- Matthieu Roulleaux Dugage
- Département d’Innovation Thérapeutique et des Essais Précoces (DITEP), Gustave Roussy, Université Paris Saclay, Villejuif, France
| | - Elise F. Nassif
- Département d’Innovation Thérapeutique et des Essais Précoces (DITEP), Gustave Roussy, Université Paris Saclay, Villejuif, France
| | - Antoine Italiano
- Département d’Innovation Thérapeutique et des Essais Précoces (DITEP), Gustave Roussy, Université Paris Saclay, Villejuif, France
- Département d’Oncologie Médicale, Institut Bergonié, Bordeaux, France
| | - Rastislav Bahleda
- Département d’Innovation Thérapeutique et des Essais Précoces (DITEP), Gustave Roussy, Université Paris Saclay, Villejuif, France
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28
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Lin Z, Xu Y, Zhang X, Wan J, Zheng T, Chen H, Chen S, Liu T. Identification and Validation of Pyroptosis-Related lncRNA Signature and Its Correlation with Immune Landscape in Soft Tissue Sarcomas. Int J Gen Med 2021; 14:8263-8279. [PMID: 34815699 PMCID: PMC8605873 DOI: 10.2147/ijgm.s335073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 11/04/2021] [Indexed: 12/17/2022] Open
Abstract
Background Pyroptosis is critically associated with cancer initiation and progression, which can be modulated by diverse long noncoding RNAs (lncRNAs). However, the roles of pyroptosis-related lncRNAs in soft tissue sarcomas (STS) are still largely unknown. Methods Our study included a total of 259 STS patients extracted from The Cancer Genome Atlas Sarcoma (TCGA-SARC) dataset. Gene expression data fragments per kilobase of transcript per million mapped reads (FPKM) values were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) for the investigation of the expression pattern of pyroptosis-related lncRNAs. Unsupervised clustering based on pyroptosis-related lncRNAs was performed, and the associations of pyroptosis-related lncRNAs with clinical outcomes and immune microenvironment were investigated. Two risk signatures for overall survival (OS) and disease-free survival (DFS) were constructed and validated in independent cohorts. Results A total of 166 pyroptosis-related lncRNAs were identified in STS. Patients were clustered into two subgroups by unsupervised clustering, and cluster 2 had better prognoses, higher immune scores, higher abundance of immune cells, and higher expression of some immune checkpoints. OS- and DFS-risk signatures based on 10 and 13 pyroptosis-related lncRNAs, respectively, with favorable discrimination were constructed and validated. High-risk patients had favorable prognoses, and receiver operating characteristic (ROC) curves showed that both risk signatures could function as excellent predictors for prognoses of STS patients. Besides, the OS-risk signature could also excellently predict the immune landscape of STS. Conclusion In conclusion, our study revealed the clinical significance and critical roles of pyroptosis-related lncRNAs in STS, and constructed novel risk signatures based on pyroptosis-related lncRNAs that could effectively predict clinical outcomes and immune microenvironment in STS.
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Affiliation(s)
- Zhengjun Lin
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China.,Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Yiting Xu
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Xianghong Zhang
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Jia Wan
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Tao Zheng
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Hongxuan Chen
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Shijie Chen
- Department of Orthopedics, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Tang Liu
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
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29
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Wang YH, Hou HA, Lin CC, Kuo YY, Yao CY, Hsu CL, Tseng MH, Tsai CH, Peng YL, Kao CJ, Chou WC, Tien HF. A CIBERSORTx-based immune cell scoring system could independently predict the prognosis of patients with myelodysplastic syndromes. Blood Adv 2021; 5:4535-4548. [PMID: 34614508 PMCID: PMC8759137 DOI: 10.1182/bloodadvances.2021005141] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 09/01/2021] [Indexed: 12/18/2022] Open
Abstract
Aside from cell intrinsic factors such as genetic alterations, immune dysregulation in the bone marrow (BM) microenvironment plays a role in the development and progression of myelodysplastic syndromes (MDS). However, the prognostic implications of various immune cells in patients with MDS remain unclear. We adopted CIBERSORTx to estimate the relative fractions of 22 subtypes of immune cells in the BM of 316 patients with MDS and correlated the results with clinical outcomes. A lower fraction of unpolarized M0 macrophages and higher fractions of M2 macrophages and eosinophils were significantly associated with inferior survival. An immune cell scoring system (ICSS) was constructed based on the proportion of these 3 immune cells in the BM. The ICSS high-risk patients had higher BM blast counts, higher frequencies of poor-risk cytogenetics, and more NPM1, TP53, and WT1 mutations than intermediate- and low-risk patients. The ICSS could stratify patients with MDS into 3 risk groups with distinct leukemia-free survival and overall survival among the total cohort and in the subgroups of patients with lower and higher disease risk based on the revised International Prognostic Scoring System (IPSS-R). The prognostic significance of ICSS was also validated in another independent cohort. Multivariable analysis revealed that ICSS independently predicted prognosis, regardless of age, IPSS-R, and mutation status. Bioinformatic analysis demonstrated a significant correlation between high-risk ICSS and nuclear factor κB signaling, oxidative stress, and leukemic stem cell signature pathways. Further studies investigating the mechanistic insight into the crosstalk between stem cells and immune cells are warranted.
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Affiliation(s)
- Yu-Hung Wang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsin-An Hou
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chien-Chin Lin
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yuan-Yeh Kuo
- Tai-Cheng Stem Cell Therapy Center, National Taiwan University, Taipei, Taiwan; and
| | - Chi-Yuan Yao
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Lang Hsu
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Mei-Hsuan Tseng
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Hong Tsai
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Ling Peng
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chein-Jun Kao
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wen-Chien Chou
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Hwei-Fang Tien
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Zhang L, Tang X, Wan J, Zhang X, Zheng T, Lin Z, Liu T. Construction of a Novel Signature and Prediction of the Immune Landscape in Soft Tissue Sarcomas Based on N6-Methylandenosine-Related LncRNAs. Front Mol Biosci 2021; 8:715764. [PMID: 34733885 PMCID: PMC8559337 DOI: 10.3389/fmolb.2021.715764] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 09/28/2021] [Indexed: 12/21/2022] Open
Abstract
Background: N6-methylandenosine-related long non-coding RNAs (m6A-related lncRNAs) are critically involved in cancer development. However, the roles and clinical significance of m6A-related lncRNAs in soft tissue sarcomas (STS) are inconclusive, thereby warranting further investigations. Methods: Transcriptome profiling data were extracted from The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx). Consensus clustering was employed to divide patients into clusters and Kaplan–Meier analysis was used to explore the prognostic differences between the subgroups. Gene set enrichment analysis (GSEA) was conducted to identify the biological processes and signaling pathways associated with m6A-Related lncRNAs. Finally, patients were randomly divided into training and validation cohorts, and least absolute shrinkage and selection operator (LASSO) Cox regression was conducted to establish the m6A-related lncRNA-based risk signature. Results: A total of 259 STS patients from TCGA-SARC dataset were enrolled in our study. Thirteen m6A-Related lncRNAs were identified to be closely related to the prognosis of STS patients. Patients were divided into two clusters, and patients in cluster 2 had a better overall survival (OS) than those in cluster 1. Patients in different clusters also showed differences in immune scores, infiltrating immune cells, and immune checkpoint expression. Patients were further classified into high-risk and low-risk subgroups according to risk scores, and high-risk patients were found to have a worse prognosis. The receiver operating characteristic (ROC) curve indicated that the risk signature displayed excellent performance at predicting the prognosis of patients with STS. Further, the risk signature was remarkably connected with the immune microenvironment and chemosensitivity in STS. Conclusion: Our study demonstrated that m6A-related lncRNAs were significantly associated with prognosis and tumor immune microenvironment and could function as independent prognosis-specific predictors in STS, thereby providing novel insights into the roles of m6A-related lncRNAs in STS.
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Affiliation(s)
- Li Zhang
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Endocrinology, The Fifth Central Hospital of Tianjin, Tianjin, China
| | - Xianzhe Tang
- Department of Orthopedics, Chenzhou No. 1 People's Hospital, Chenzhou, China
| | - Jia Wan
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xianghong Zhang
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Tao Zheng
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhengjun Lin
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Tang Liu
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, China
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31
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Wei Y, Yang X, Gao L, Yang J, Zheng L, Gao L, Zhou X, Xiang X, Zhang J, Yi C. Identification of potential immune-related circRNA-miRNA-mRNA regulatory network in cutaneous squamous cell carcinoma. Am J Cancer Res 2021; 11:4826-4843. [PMID: 34765295 PMCID: PMC8569358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 09/21/2021] [Indexed: 06/13/2023] Open
Abstract
Circulating RNAs (circRNAs) are involved in tumor development and progression by participating in immune regulation. Nevertheless, the circRNAs expression profiles and their roles on the immunomodulatory effects in cutaneous squamous cell carcinoma (cSCC) have rarely been studied. In our study, we identified the differentially expressed circRNAs (DEcircRNAs), miRNAs (DEmiRNAs), mRNAs (DEmRNAs) in cSCC and established the circRNA competing endogenous RNAs (ceRNAs) network. Subsequently, the hub differentially expressed immune-related genes were identified and validated by immunochemistry as well as the GO and KEGG pathway analysis were performed. 54 differentially expressed circRNAs were identified and hub differentially expressed immune-related genes were identified and they were mostly associated with immune response in the progression of cSCC. Our results indicated that the potential immune-related circRNA-miRNA-mRNA network may assist in understanding the molecular mechanisms underlying the carcinogenesis and progression in cSCC. Moreover, the immune-related genes may provide an insight into the pathogenesis, molecular biomarkers, and potential therapeutic targets for cSCC patients.
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Affiliation(s)
- Yuanfeng Wei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Xi Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Limin Gao
- Department of Pathology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Ju Yang
- Department of Pathophysiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Lingnan Zheng
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Ling Gao
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Xiaohan Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Xiaoyu Xiang
- Department of Pathology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Jie Zhang
- Lab of Experimental Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation CenterChengdu 610041, Sichuan, China
| | - Cheng Yi
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
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Yin X, Wang Z, Wang J, Xu Y, Kong W, Zhang J. Development of a novel gene signature to predict prognosis and response to PD-1 blockade in clear cell renal cell carcinoma. Oncoimmunology 2021; 10:1933332. [PMID: 34262797 PMCID: PMC8253123 DOI: 10.1080/2162402x.2021.1933332] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 05/18/2021] [Indexed: 12/22/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common kidney malignancy characterized by a poor prognosis. The treatment efficacy of immune checkpoint inhibitors (ICIs) also varies widely in advanced ccRCC. We aim to construct a robust gene signature to improve the prognostic discrimination and prediction of ICIs for ccRCC patients. In this study, adopting differentially expressed genes from seven ccRCC datasets in GEO (Gene Expression Omnibus), a novel signature (FOXM1&TOP2A) was constructed in TCGA (The Cancer Genome Atlas) database by LASSO and Cox regression. Survival and time-dependent ROC analysis revealed the strong predictive ability of our signature in discovery set, two online validation sets and one tissue microarray (TMA) from our institution. High-risk group based on the signature comprises more high-grade (G3&G4) and advanced pathologic stage (stageIII/IV) tumors and presents hyperactivation of cell cycle process according to the functional analysis. Meanwhile, high-risk tumors demonstrate an immunosuppressive phenotype with more infiltrations of regulatory T cells (Tregs), macrophages and high expressions of genes negatively regulating anti-tumor immunity. Low-risk tumors have an improved response to anti-PD-1 therapy and the predictive ability of our signature is better than other recognized biomarkers in ccRCC. A nomogram containing this signature showed a high predictive accuracy with AUCs of 0.90 and 0.84 at 3 and 5 years. Overall, this robust signature could predict prognosis, evaluate immune microenvironment and response to anti-PD-1 therapy in ccRCC, which is very promising in clinical promotion.
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Affiliation(s)
- Xiaomao Yin
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Zaoyu Wang
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jianfeng Wang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yunze Xu
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Wen Kong
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jin Zhang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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Zheng H, Bai Y, Wang J, Chen S, Zhang J, Zhu J, Liu Y, Wang X. Weighted Gene Co-expression Network Analysis Identifies CALD1 as a Biomarker Related to M2 Macrophages Infiltration in Stage III and IV Mismatch Repair-Proficient Colorectal Carcinoma. Front Mol Biosci 2021; 8:649363. [PMID: 33996905 PMCID: PMC8116739 DOI: 10.3389/fmolb.2021.649363] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/23/2021] [Indexed: 12/24/2022] Open
Abstract
Immunotherapy has achieved efficacy for advanced colorectal cancer (CRC) patients with a mismatch-repair-deficient (dMMR) subtype. However, little immunotherapy efficacy was observed in patients with the mismatch repair-proficient (pMMR) subtype, and hence, identifying new immune therapeutic targets is imperative for those patients. In this study, transcriptome data of stage III/IV CRC patients were retrieved from the Gene Expression Omnibus database. The CIBERSORT algorithm was used to quantify immune cellular compositions, and the results revealed that M2 macrophage fractions were higher in pMMR patients as compared with those with the dMMR subtype; moreover, pMMR patients with higher M2 macrophage fractions experienced shorter overall survival (OS). Subsequently, weighted gene co-expression network analysis and protein–protein interaction network analysis identified six hub genes related to M2 macrophage infiltrations in pMMR CRC patients: CALD1, COL6A1, COL1A2, TIMP3, DCN, and SPARC. Univariate and multivariate Cox regression analyses then determined CALD1 as the independent prognostic biomarker for OS. CALD1 was upregulated specifically the in CMS4 CRC subtype, and single-sample Gene Set Enrichment Analysis (ssGSEA) revealed that CALD1 was significantly correlated with angiogenesis and TGF-β signaling gene sets enrichment scores in stage III/IV pMMR CRC samples. The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm and correlation analysis revealed that CALD1 was significantly associated with multiple immune and stromal components in a tumor microenvironment. In addition, GSEA demonstrated that high expression of CALD1 was significantly correlated with antigen processing and presentation, chemokine signaling, leukocyte transendothelial migration, vascular smooth muscle contraction, cytokine–cytokine receptor interaction, cell adhesion molecules, focal adhesion, MAPK, and TGF-beta signaling pathways. Furthermore, the proliferation, invasion, and migration abilities of cancer cells were suppressed after reducing CALD1 expression in CRC cell lines. Taken together, multiple bioinformatics analyses and cell-level assays demonstrated that CALD1 could serve as a prognostic biomarker and a prospective therapeutic target for stage III/IV pMMR CRCs.
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Affiliation(s)
- Hang Zheng
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yuge Bai
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Jingui Wang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Shanwen Chen
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Junling Zhang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Jing Zhu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yucun Liu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Xin Wang
- Department of General Surgery, Peking University First Hospital, Beijing, China
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Li Z, Liu Y, Jia A, Cui Y, Feng J. Cerebrospinal fluid cells immune landscape in multiple sclerosis. J Transl Med 2021; 19:125. [PMID: 33766068 PMCID: PMC7995713 DOI: 10.1186/s12967-021-02804-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/19/2021] [Indexed: 02/06/2023] Open
Abstract
Background Multiple Sclerosis (MS) is a potentially devastating autoimmune neurological disorder, which characteristically induces demyelination of white matter in the brain and spinal cord. Methods In this study, three characteristics of the central nervous system (CNS) immune microenvironment occurring during MS onset were explored; immune cell proportion alteration, differential gene expression profile, and related pathways. The raw data of two independent datasets were obtained from the ArrayExpress database; E-MTAB-69, which was used as a derivation cohort, and E-MTAB-2374 which was used as a validation cohort. Differentially expressed genes (DEGs) were identified by the false discovery rate (FDR) value of < 0.05 and |log2 (Fold Change)|> 1, for further analysis. Then, functional enrichment analyses were performed to explore the pathways associated with MS onset. The gene expression profiles were analyzed using CIBERSORT to identify the immune type alterations involved in MS disease. Results After verification, the proportion of five types of immune cells (plasma cells, monocytes, macrophage M2, neutrophils and eosinophils) in cerebrospinal fluid (CSF) were revealed to be significantly altered in MS cases compared to the control group. Thus, the complement and coagulation cascades and the systemic lupus erythematosus (SLE) pathways may play critical roles in MS. We identified NLRP3, LILRB2, C1QB, CD86, C1QA, CSF1R, IL1B and TLR2 as eight core genes correlated with MS. Conclusions Our study identified the change in the CNS immune microenvironment of MS cases by analysis of the in silico data using CIBERSORT. Our data may assist in providing directions for further research as to the molecular mechanisms of MS and provide future potential therapeutic targets in treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02804-7.
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Affiliation(s)
- Zijian Li
- Department of Neurology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, China
| | - Yongchao Liu
- Department of Neurology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, China
| | - Aili Jia
- Department of Neurology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, China
| | - Yueran Cui
- Department of Neurology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, China
| | - Juan Feng
- Department of Neurology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, China.
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Shen R, Liu B, Li X, Yu T, Xu K, Ma J. Development and validation of an immune gene-set based prognostic signature for soft tissue sarcoma. BMC Cancer 2021; 21:144. [PMID: 33557781 PMCID: PMC7871579 DOI: 10.1186/s12885-021-07852-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 01/27/2021] [Indexed: 12/12/2022] Open
Abstract
Background Sarcomas is a group of heterogeneous malignant tumors originated from mesenchymal tissue and different types of sarcomas have disparate outcomes. The present study aims to identify the prognostic value of immune-related genes (IRGs) in sarcoma and establish a prognostic signature based on IRGs. Methods We collected the expression profile and clinical information of 255 soft tissue sarcoma samples from The Cancer Genome Atlas (TCGA) database and 2498 IRGs from the ImmPort database. The LASSO algorithm and Cox regression analysis were used to identify the best candidate genes and construct a signature. The prognostic ability of the signature was evaluated by ROC curves and Kaplan-Meier survival curves and validated in an independent cohort. Besides, a nomogram based on the IRGs and independent prognostic clinical variables was developed. Results A total of 19 IRGs were incorporated into the signature. In the training cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.938, 0.937 and 0.935, respectively. The Kaplan-Meier survival curve indicated that high-risk patients were significantly worse prognosis (P < 0.001). In the validation cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.730, 0.717 and 0.647, respectively. The Kaplan-Meier survival curve also showed significant distinct survival outcome between two risk groups. Furthermore, a nomogram based on the signature and four prognostic variables showed great accuracy in whole sarcoma patients and subgroup analyses. More importantly, the results of the TF regulatory network and immune infiltration analysis revealed the potential molecular mechanism of IRGs. Conclusions In general, we identified and validated an IRG-based signature, which can be used as an independent prognostic signature in evaluating the prognosis of sarcoma patients and provide potential novel immunotherapy targets. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-07852-2.
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Affiliation(s)
- Rui Shen
- Department of Spinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Bo Liu
- Department of Spinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Xuesen Li
- Department of Spinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Tengbo Yu
- Department of Sport Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Kuishuai Xu
- Department of Sport Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Jinfeng Ma
- Department of Spinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
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