Integrating single-cell RNA-seq and bulk RNA-seq to explore prognostic value and immune landscapes of methionine metabolism-related signature in breast cancer
BackgroundNeoadjuvant, endocrine, and targeted therapies have significantly improved the prognosis of breast cancer (BC). However, due to the high heterogeneity of cancer, some patients cannot benefit from existing treatments. Increasing evidence suggests that amino acids and their metabolites can a...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2024.1521269/full |
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| author | Yanxian Gao Ziyu Feng Hailong Zhao Xinghai Liu Muyu Zhu Xiafei Yu Xiaoan Liu Xian Wu Jing Tao |
| author_facet | Yanxian Gao Ziyu Feng Hailong Zhao Xinghai Liu Muyu Zhu Xiafei Yu Xiaoan Liu Xian Wu Jing Tao |
| author_sort | Yanxian Gao |
| collection | DOAJ |
| description | BackgroundNeoadjuvant, endocrine, and targeted therapies have significantly improved the prognosis of breast cancer (BC). However, due to the high heterogeneity of cancer, some patients cannot benefit from existing treatments. Increasing evidence suggests that amino acids and their metabolites can alter the tumor malignant behavior through reshaping tumor microenvironment and regulation of immune cell function. Breast cancer cell lines have been identified as methionine-dependent, and methionine restriction has been proposed as a potential cancer treatment strategy.MethodsWe integrated transcriptomic and single-cell RNA sequencing (ScRNA-seq) analyses based on The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. Then we applied weighted gene co-expression network analysis (WGCNA) and Cox regression to evaluate methionine metabolism-related genes (MRGs) in BC, constructing and validating a prognostic model for BC patients. Immune landscapes and immunotherapy were further explored. Finally, in vitro experiments were conducted to assess the expression and function of key genes APOC1.ResultsIn this study, we established and validated a prognostic signature based on eight methionine-related genes to predict overall survival (OS) in BC patients. Patients were further stratified into high-risk and low-risk groups according to prognostic risk score. Further analysis revealed significant differences between two groups in terms of pathway alterations, immune microenvironment characteristics, and immune checkpoint expression. Our study shed light on the relationship between methionine metabolism and immune infiltration in BC. APOC1, a key gene in the prognostic signature, was found to be upregulated in BC and closely associated with immune cell infiltration. Notably, APOC1 was primarily expressed in macrophages. Subsequent in vitro experiments demonstrated that silencing APOC1 reduced the generation of tumor-associated macrophages (TAMs) with an M2 phenotype while significantly decreasing the proliferation, invasion, and migration of MDA-MB-231 and MDA-MB-468 breast cancer cell lines.ConclusionWe established a prognostic risk score consisting of genes associated with methionine metabolism, which helps predict prognosis and response to treatment in BC. The function of APOC1 in regulating macrophage polarization was explored. |
| format | Article |
| id | doaj-art-bbb5235387dc4ea6853bbe46a0be124b |
| institution | Kabale University |
| issn | 1664-8021 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj-art-bbb5235387dc4ea6853bbe46a0be124b2025-01-14T06:10:40ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-01-011510.3389/fgene.2024.15212691521269Integrating single-cell RNA-seq and bulk RNA-seq to explore prognostic value and immune landscapes of methionine metabolism-related signature in breast cancerYanxian Gao0Ziyu Feng1Hailong Zhao2Xinghai Liu3Muyu Zhu4Xiafei Yu5Xiaoan Liu6Xian Wu7Jing Tao8Breast Disease Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, ChinaBreast Disease Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, ChinaDepartment of General Surgery, Huangyuan People’s Hospital, Xining, Qinghai, ChinaBreast Disease Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, ChinaBreast Disease Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, ChinaBreast Disease Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, ChinaBreast Disease Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, ChinaBreast Disease Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, ChinaDepartment of General Surgery, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, ChinaBackgroundNeoadjuvant, endocrine, and targeted therapies have significantly improved the prognosis of breast cancer (BC). However, due to the high heterogeneity of cancer, some patients cannot benefit from existing treatments. Increasing evidence suggests that amino acids and their metabolites can alter the tumor malignant behavior through reshaping tumor microenvironment and regulation of immune cell function. Breast cancer cell lines have been identified as methionine-dependent, and methionine restriction has been proposed as a potential cancer treatment strategy.MethodsWe integrated transcriptomic and single-cell RNA sequencing (ScRNA-seq) analyses based on The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. Then we applied weighted gene co-expression network analysis (WGCNA) and Cox regression to evaluate methionine metabolism-related genes (MRGs) in BC, constructing and validating a prognostic model for BC patients. Immune landscapes and immunotherapy were further explored. Finally, in vitro experiments were conducted to assess the expression and function of key genes APOC1.ResultsIn this study, we established and validated a prognostic signature based on eight methionine-related genes to predict overall survival (OS) in BC patients. Patients were further stratified into high-risk and low-risk groups according to prognostic risk score. Further analysis revealed significant differences between two groups in terms of pathway alterations, immune microenvironment characteristics, and immune checkpoint expression. Our study shed light on the relationship between methionine metabolism and immune infiltration in BC. APOC1, a key gene in the prognostic signature, was found to be upregulated in BC and closely associated with immune cell infiltration. Notably, APOC1 was primarily expressed in macrophages. Subsequent in vitro experiments demonstrated that silencing APOC1 reduced the generation of tumor-associated macrophages (TAMs) with an M2 phenotype while significantly decreasing the proliferation, invasion, and migration of MDA-MB-231 and MDA-MB-468 breast cancer cell lines.ConclusionWe established a prognostic risk score consisting of genes associated with methionine metabolism, which helps predict prognosis and response to treatment in BC. The function of APOC1 in regulating macrophage polarization was explored.https://www.frontiersin.org/articles/10.3389/fgene.2024.1521269/fullAPOC1 genemethionine metabolismbreast cancersingle-cell sequencing (scRNA-seq)prognostic signaturetumor immune microenvironment (TIME) |
| spellingShingle | Yanxian Gao Ziyu Feng Hailong Zhao Xinghai Liu Muyu Zhu Xiafei Yu Xiaoan Liu Xian Wu Jing Tao Integrating single-cell RNA-seq and bulk RNA-seq to explore prognostic value and immune landscapes of methionine metabolism-related signature in breast cancer Frontiers in Genetics APOC1 gene methionine metabolism breast cancer single-cell sequencing (scRNA-seq) prognostic signature tumor immune microenvironment (TIME) |
| title | Integrating single-cell RNA-seq and bulk RNA-seq to explore prognostic value and immune landscapes of methionine metabolism-related signature in breast cancer |
| title_full | Integrating single-cell RNA-seq and bulk RNA-seq to explore prognostic value and immune landscapes of methionine metabolism-related signature in breast cancer |
| title_fullStr | Integrating single-cell RNA-seq and bulk RNA-seq to explore prognostic value and immune landscapes of methionine metabolism-related signature in breast cancer |
| title_full_unstemmed | Integrating single-cell RNA-seq and bulk RNA-seq to explore prognostic value and immune landscapes of methionine metabolism-related signature in breast cancer |
| title_short | Integrating single-cell RNA-seq and bulk RNA-seq to explore prognostic value and immune landscapes of methionine metabolism-related signature in breast cancer |
| title_sort | integrating single cell rna seq and bulk rna seq to explore prognostic value and immune landscapes of methionine metabolism related signature in breast cancer |
| topic | APOC1 gene methionine metabolism breast cancer single-cell sequencing (scRNA-seq) prognostic signature tumor immune microenvironment (TIME) |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2024.1521269/full |
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