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Open accessJournal ArticleDOI: 10.1038/S41467-021-21514-8

RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming.

02 Mar 2021-Nature Communications (Springer Science and Business Media LLC)-Vol. 12, Iss: 1, pp 1394-1394
Abstract: N6-methyladenosine (m6A) is a reversible mRNA modification that has been shown to play important roles in various biological processes. However, the roles of m6A modification in macrophages are still unknown. Here, we discover that ablation of Mettl3 in myeloid cells promotes tumour growth and metastasis in vivo. In contrast to wild-type mice, Mettl3-deficient mice show increased M1/M2-like tumour-associated macrophage and regulatory T cell infiltration into tumours. m6A sequencing reveals that loss of METTL3 impairs the YTHDF1-mediated translation of SPRED2, which enhances the activation of NF-kB and STAT3 through the ERK pathway, leading to increased tumour growth and metastasis. Furthermore, the therapeutic efficacy of PD-1 checkpoint blockade is attenuated in Mettl3-deficient mice, identifying METTL3 as a potential therapeutic target for tumour immunotherapy.

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Topics: MRNA modification (56.99%), Tumor microenvironment (55%), Metastasis (53%) ... show more
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7 results found


Open accessJournal ArticleDOI: 10.1186/S13045-021-01129-8
Wei Huang1, Tian-Qi Chen1, Ke Fang1, Zhan-Cheng Zeng1  +2 moreInstitutions (1)
Abstract: N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects the fates of modified RNAs, including their stability, splicing, and/or translation, and thus plays important roles in posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute m6A deposition on distinct RNAs by their own or forming different complexes with additional partner proteins. In this review, we summarize the function of these m6A methyltransferases or complexes in regulating the key genes and pathways of cancer biology. We also highlight the progress in the use of m6A methyltransferases in mediating therapy resistance, including chemotherapy, targeted therapy, immunotherapy and radiotherapy. Finally, we discuss the current approaches and clinical potential of m6A methyltransferase-targeting strategies.

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Topics: Methyltransferase (57.99%)

1 Citations


Open accessJournal ArticleDOI: 10.3389/FONC.2021.720400
Wenting Zhou1, Chen Bai1, Chaojun Long1, Li Hu1  +1 moreInstitutions (1)
Abstract: Lung adenocarcinoma (LUAD) is one type of the malignant tumors with high morbidity and mortality. The molecular mechanism of LUAD is still unclear. Studies demonstrate that lncRNAs play crucial roles in LUAD tumorigenesis and can be used as prognosis biomarkers. Thus, in this study, to identify more robust biomarkers of LUAD, we firstly constructed LUAD-related lncRNA-TF network and performed topological analyses for the network. Results showed that the network was a scale-free network, and some hub genes with high clinical values were identified, such as lncRNA RP11-173A16 and TF ZBTB37. Module analysis on the network revealed one close lncRNA module, which had good prognosis performance in LUAD. Furthermore, through integrating ceRNAs strategy and TF regulatory information, we identified some lncRNA-TF positive feedback loops. Prognostic analysis revealed that ELK4- and BDP1-related feedback loops were significant. Secondly, we constructed the lncRNA-m6A regulator network by merging all the high correlated lncRNA-m6A regulator pairs. Based on the network analysis results, some key m6A-related lncRNAs were identified, such as MIR497HG, FENDRR, and RP1-199J3. We also investigated the relationships between these lncRNAs and immune cell infiltration. Results showed that these m6A-related lncRNAs were high correlated with tumor immunity. All these results provide a new perspective for the diagnostic biomarker and therapeutic target identification of LUAD.

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Open accessJournal ArticleDOI: 10.3389/FCELL.2021.736298
Lei Zhan, Junhui Zhang1, Junhui Zhang2, Suding Zhu1  +8 moreInstitutions (2)
Abstract: Immunotherapy is a novel clinical approach that has shown clinical efficacy in multiple cancers. However, only a fraction of patients respond well to immunotherapy. Immuno-oncological studies have identified the type of tumors that are sensitive to immunotherapy, the so-called hot tumors, while unresponsive tumors, known as "cold tumors," have the potential to turn into hot ones. Therefore, the mechanisms underlying cold tumor formation must be elucidated, and efforts should be made to turn cold tumors into hot tumors. N6-methyladenosine (m6A) RNA modification affects the maturation and function of immune cells by controlling mRNA immunogenicity and innate immune components in the tumor microenvironment (TME), suggesting its predominant role in the development of tumors and its potential use as a target to improve cancer immunotherapy. In this review, we first describe the TME, cold and hot tumors, and m6A RNA modification. Then, we focus on the role of m6A RNA modification in cold tumor formation and regulation. Finally, we discuss the potential clinical implications and immunotherapeutic approaches of m6A RNA modification in cancer patients. In conclusion, m6A RNA modification is involved in cold tumor formation by regulating immunity, tumor-cell-intrinsic pathways, soluble inhibitory mediators in the TME, increasing metabolic competition, and affecting the tumor mutational burden. Furthermore, m6A RNA modification regulators may potentially be used as diagnostic and prognostic biomarkers for different types of cancer. In addition, targeting m6A RNA modification may sensitize cancers to immunotherapy, making it a promising immunotherapeutic approach for turning cold tumors into hot ones.

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Open accessJournal ArticleDOI: 10.1016/J.JARE.2021.10.001
Hui Yang1, Yiren Hu1, Yiren Hu2, Mingzhe Weng1  +10 moreInstitutions (4)
Abstract: Introduction Tumors are usually refractory to anti-cancer therapeutics under hypoxic conditions. However, the underlying molecular mechanism remains to be elucidated. Objectives Our study intended to identify hypoxia inducible lncRNAs and their biological function in gastric cancer (GC). Methods Differentially expressed lncRNAs were determined by microarray analysis between GC cells exposed to hypoxia (1% O2) and normoxia (21% O2) for 24 h. The expression level of CBSLR was manipulated in several GC cell lines to perform molecular and biological analyses both in vitro and in vivo. Results We identified a hypoxia-induced lncRNA-CBSLR that protected GC cells from ferroptosis, leading to chem-resistance. Mechanically, CBSLR interacted with YTHDF2 to form a CBSLR/YTHDF2/CBS signaling axis that decreased the stability of CBS mRNA by enhancing the binding of YTHDF2 with the m6A-modified coding sequence (CDS) of CBS mRNA. Furthermore, under decreased CBS levels, the methylation of the ACSL4 protein was reduced, leading to protein polyubiquitination and degradation of ACSL4. This, in turn, decreased the pro-ferroptosis phosphatidylethanolamine (PE) (18:0/20:4) and PE (18:0/22:4) content and contributed to ferroptosis resistance. Notably, CBSLR is upregulated, whereas CBS is downregulated in GC tissues compared to matched normal tissues; and GC patients with high CBSLR/low CBS levels have a worse clinical outcome and a poorer response to chemotherapy. Conclusion Our study reveals a novel mechanism in how HIF1α/CBSLR modulates ferroptosis/chemoresistance in GC, illuminating potential therapeutic targets for refractory hypoxic tumors.

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Open accessJournal ArticleDOI: 10.3389/FIMMU.2021.762564
Zhending Gan1, Meiyu Zhang, Donghui Xie, Xiaoyan Wu1  +5 moreInstitutions (1)
Abstract: Accumulating evidences support that amino acids direct the fate decision of immune cells. Glycine is a simple structural amino acid acting as an inhibitory neurotransmitter. Besides, glycine receptors as well as glycine transporters are found in macrophages, indicating that glycine alters the functions of macrophages besides as an inhibitory neurotransmitter. Mechanistically, glycine shapes macrophage polarization via cellular signaling pathways (e.g., NF-κB, NRF2, and Akt) and microRNAs. Moreover, glycine has beneficial effects in preventing and/or treating macrophage-associated diseases such as colitis, NAFLD and ischemia-reperfusion injury. Collectively, this review highlights the conceivable role of glycinergic signaling for macrophage polarization and indicates the potential application of glycine supplementation as an adjuvant therapy in macrophage-associated diseases.

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Topics: Glycine receptor (61%), Macrophage polarization (60%), Glycine (59%) ... show more

References
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57 results found


Open accessJournal ArticleDOI: 10.1016/J.CELL.2010.01.025
19 Mar 2010-Cell
Abstract: Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. Inflammation also affects immune surveillance and responses to therapy. Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, and some of the molecular events that mediate this dialog have been revealed. This review outlines the principal mechanisms that govern the effects of inflammation and immunity on tumor development and discusses attractive new targets for cancer therapy and prevention.

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Topics: Immune system (53%), Metastasis (53%), Inflammation (52%)

7,334 Citations


Open accessJournal ArticleDOI: 10.1038/NRI2506
Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

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Topics: Acquired immune system (61%), Myeloid-derived Suppressor Cell (59%), Innate immune system (57.99%) ... show more

5,072 Citations


Journal ArticleDOI: 10.1038/NM1093
Tyler J. Curiel1, George Coukos2, Linhua Zou1, Xavier Alvarez1  +17 moreInstitutions (5)
22 Aug 2004-Nature Medicine
Abstract: Regulatory T (T(reg)) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen-reactive lymphocytes mediated by T(reg) cells; however, definitive evidence that T(reg) cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4(+)CD25(+)FOXP3(+) T(reg) cells in 104 individuals affected with ovarian carcinoma, that human tumor T(reg) cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor T(reg) cells are associated with a high death hazard and reduced survival. Human T(reg) cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of T(reg) cells to the tumor. This specific recruitment of T(reg) cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking T(reg) cell migration or function may help to defeat human cancer.

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Topics: Cytotoxic T cell (65%), Peripheral tolerance (64%), IL-2 receptor (64%) ... show more

4,465 Citations


Open accessJournal ArticleDOI: 10.1016/J.IMMUNI.2014.06.008
17 Jul 2014-Immunity
Abstract: Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated macrophages, often termed M1 and M2. Here, we describe a set of standards encompassing three principles—the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation—with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for macrophage-activation nomenclature.

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Topics: Macrophage polarization (53%)

3,340 Citations


Open accessJournal ArticleDOI: 10.12703/P6-13
Fernando O. Martinez1, Siamon Gordon1Institutions (1)
Abstract: Macrophages are endowed with a variety of receptors for lineage-determining growth factors, T helper (Th) cell cytokines, and B cell, host, and microbial products. In tissues, macrophages mature and are activated in a dynamic response to combinations of these stimuli to acquire specialized functional phenotypes. As for the lymphocyte system, a dichotomy has been proposed for macrophage activation: classic vs. alternative, also M1 and M2, respectively. In view of recent research about macrophage functions and the increasing number of immune-relevant ligands, a revision of the model is needed. Here, we assess how cytokines and pathogen signals influence their functional phenotypes and the evidence for M1 and M2 functions and revisit a paradigm initially based on the role of a restricted set of selected ligands in the immune response.

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Topics: Macrophage (53%), B cell (52%), Immune system (51%)

3,004 Citations


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20217