Cellular plasticity and drug resistance in sarcoma

Lin, Zhengjun; Zhai, Fan; Zhang, Xianghong; Wan, Jia

doi:10.1016/j.lfs.2020.118589

Cited by 22 publications

(23 citation statements)

References 141 publications

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“…Commonly used chemotherapeutic drugs for STS include doxorubicin, ifosfamide, and gemcitabine ( Ratan and Patel, 2016 ). However, the development of chemoresistance has become the main obstacle in the improvement of chemotherapeutic efficacy and prognosis of patients with STS ( Lin et al, 2020 ). Thus, it is critical to develop effective biomarkers to predict chemosensitivity and novel therapeutic targets to reverse chemoresistance in STS.…”

Section: Discussionmentioning

confidence: 99%

Construction of a Novel Signature and Prediction of the Immune Landscape in Soft Tissue Sarcomas Based on N6-Methylandenosine-Related LncRNAs

Zhang

Tang

Wan

et al. 2021

Front. Mol. Biosci.

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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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Section: Discussionmentioning

confidence: 99%

Construction of a Novel Signature and Prediction of the Immune Landscape in Soft Tissue Sarcomas Based on N6-Methylandenosine-Related LncRNAs

Zhang

Tang

Wan

et al. 2021

Front. Mol. Biosci.

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Section: Discussionmentioning

confidence: 99%

“…Although most sarcoma harbors distinct biologic features, the primary treatment approach for locally advanced or unresectable disease often incorporates cytotoxic chemotherapy ( Hashimoto et al, 2020 ; Heng et al, 2020 ; Lin et al, 2020 ). Recently, understanding of subtype-specific cancer biology has expanded and revealed distinct molecular alterations responsible for tumor initiation and progression ( Grünewald et al, 2020 ; Steele and Pillay, 2020 ; Zhu et al, 2020 ), so has the study on cross talk between sarcoma cells and TME, as well as the heterogeneous mechanisms of tumor immune evasion ( Becht et al, 2016 ; Pollack et al, 2018 ; Heymann et al, 2019 ; Miyake et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Development of a Novel Immune Infiltration-Related ceRNA Network and Prognostic Model for Sarcoma

Shi

et al. 2021

Front. Cell Dev. Biol.

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Due to the rarity and heterogeneity, it is challenging to explore and develop new therapeutic targets for patients with sarcoma. Recently, immune cell infiltration in the tumor microenvironment (TME) was widely studied, which provided a novel potential approach for cancer treatment. The competing endogenous RNA (ceRNA) regulatory network has been reported as a critical molecular mechanism of tumor development. However, the role of the ceRNA regulatory network in the TME of sarcoma remains unclear. In this study, gene expression data and clinical information were obtained from The Cancer Genome Atlas (TCGA) sarcoma datasets, and an immune infiltration-related ceRNA network was constructed, which comprised 14 lncRNAs, 13 miRNAs, and 23 mRNAs. Afterward, we constructed an immune infiltration-related risk score model based on the expression of IRF1, MFNG, hsa-miR-940, and hsa-miR-378a-5p, presenting a promising performance in predicting the prognosis of patients with sarcoma.

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“…One of the difficulties in cancer treatment is that tumor cells acquire resistance to treatment to which cells have been subjected. Although chemotherapy and radiotherapy can control tumor growth at first exposure, tumor cells eventually develop resistance to these treatments, resulting in tumor progression 11‐13 . In addition, several reports have indicated that immunotherapy, including ICI and chimeric antigen receptor‐T‐cell therapy, also leads to treatment‐resistant tumors through a variety of mechanisms, including loss of surface expression of MHC class I, loss‐of‐function mutations in genes encoding IFN‐γ pathway‐related proteins, and loss of expression of neoantigens and targeted antigens 14‐16 .…”

Section: Introductionmentioning

confidence: 99%

“…Although chemotherapy and radiotherapy can control tumor growth at first exposure, tumor cells eventually develop resistance to these treatments, resulting in tumor progression. [11][12][13] In addition, several reports have indicated that immunotherapy, including ICI and chimeric antigen receptor-T-cell therapy, also leads to treatment-resistant tumors through a variety of mechanisms, including loss of surface expression of MHC class I, loss-of-function mutations in genes encoding IFNγ pathway-related proteins, and loss of expression of neoantigens and targeted antigens. [14][15][16] One mechanism of antigen loss in tumor cells was revealed using a transgenic mouse model in which expression of a highly immunogenic antigen was silenced by methylation of the promoter region of a gene encoding an antigen; expression of the antigen was restored by treatment with a DNA methyltransferase inhibitor.…”

Section: Introductionmentioning

confidence: 99%

A stealth antigen SPESP1, which is epigenetically silenced in tumors, is a suitable target for cancer immunotherapy

et al. 2021

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Recent studies have revealed that tumor cells decrease their immunogenicity by epigenetically repressing the expression of highly immunogenic antigens to survive in immunocompetent hosts. We hypothesized that these epigenetically hidden “stealth” antigens should be favorable targets for cancer immunotherapy due to their high immunogenicity. To identify these stealth antigens, we treated human lung cell line A549 with DNA methyltransferase inhibitor 5‐aza‐2′‐deoxycytidine (5Aza) and its prodrug guadecitabine for 3 d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re‐expressed in cell lines including solid tumors and leukemias treated with 5Aza, although SPESP1 was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that SPESP1 was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re‐expression in xenografts in BALB/c‐nu/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4+ T‐cells with a SPESP1‐derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1‐specific helper T‐cells were obtained; these cells produced interferon‐γ against HLA‐matched tumor cell lines treated with 5Aza. We also detected SPESP1 expression in freshly collected tumor cells derived from patients with acute myeloid leukemia or lung cancer. In conclusion, SPESP1 can be classified as a stealth antigen, a molecule encoded by a gene that is epigenetically silenced in tumor cells but serves as a highly immunogenic antigen suitable for cancer immunotherapy.

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Cellular plasticity and drug resistance in sarcoma

Cited by 22 publications

References 141 publications

Construction of a Novel Signature and Prediction of the Immune Landscape in Soft Tissue Sarcomas Based on N6-Methylandenosine-Related LncRNAs

Construction of a Novel Signature and Prediction of the Immune Landscape in Soft Tissue Sarcomas Based on N6-Methylandenosine-Related LncRNAs

Development of a Novel Immune Infiltration-Related ceRNA Network and Prognostic Model for Sarcoma

A stealth antigen SPESP1, which is epigenetically silenced in tumors, is a suitable target for cancer immunotherapy

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