Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma
Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA i...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-02-01
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| Series: | Cancer Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cac2.12513 |
| _version_ | 1797302832112599040 |
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| author | Weiren Liu Huqiang Wang Qianfu Zhao Chenyang Tao Weifeng Qu Yushan Hou Run Huang Zimei Sun Guiqi Zhu Xifei Jiang Yuan Fang Jun Gao Xiaoling Wu Zhixiang Yang Rongyu Ping Jiafeng Chen Rui Yang Tianhao Chu Jian Zhou Jia Fan Zheng Tang Dong Yang Yinghong Shi |
| author_facet | Weiren Liu Huqiang Wang Qianfu Zhao Chenyang Tao Weifeng Qu Yushan Hou Run Huang Zimei Sun Guiqi Zhu Xifei Jiang Yuan Fang Jun Gao Xiaoling Wu Zhixiang Yang Rongyu Ping Jiafeng Chen Rui Yang Tianhao Chu Jian Zhou Jia Fan Zheng Tang Dong Yang Yinghong Shi |
| author_sort | Weiren Liu |
| collection | DOAJ |
| description | Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA. Methods We performed integrated multiomics analysis in 116 iCCA samples, including whole‐exome sequencing, bulk RNA‐sequencing and proteome analysis. Based on the non‐negative matrix factorization method and the protein abundance of metabolic genes in human genome‐scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5‐ethynyl‐2'‐deoxyuridine (EdU) assay, colony formation assay, RNA‐sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells. Results Three metabolic subtypes (S1‐S3) with subtype‐specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune‐suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT‐rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype‐specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen‐activated protein kinase (MAPK) signaling. Conclusion Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype. |
| first_indexed | 2024-03-07T23:44:39Z |
| format | Article |
| id | doaj.art-d68f939a8bc9449c93611c59561316a3 |
| institution | Directory Open Access Journal |
| issn | 2523-3548 |
| language | English |
| last_indexed | 2024-03-07T23:44:39Z |
| publishDate | 2024-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Communications |
| spelling | doaj.art-d68f939a8bc9449c93611c59561316a32024-02-19T19:34:34ZengWileyCancer Communications2523-35482024-02-0144222625010.1002/cac2.12513Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinomaWeiren Liu0Huqiang Wang1Qianfu Zhao2Chenyang Tao3Weifeng Qu4Yushan Hou5Run Huang6Zimei Sun7Guiqi Zhu8Xifei Jiang9Yuan Fang10Jun Gao11Xiaoling Wu12Zhixiang Yang13Rongyu Ping14Jiafeng Chen15Rui Yang16Tianhao Chu17Jian Zhou18Jia Fan19Zheng Tang20Dong Yang21Yinghong Shi22Department of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaState Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics Beijing P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaState Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics Beijing P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaState Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics Beijing P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaState Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics Beijing P. R. ChinaState Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics Beijing P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaState Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics Beijing P. R. ChinaDepartment of Liver Surgery and Transplantation Liver Cancer Institute, Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai P. R. ChinaAbstract Background Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA. Methods We performed integrated multiomics analysis in 116 iCCA samples, including whole‐exome sequencing, bulk RNA‐sequencing and proteome analysis. Based on the non‐negative matrix factorization method and the protein abundance of metabolic genes in human genome‐scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5‐ethynyl‐2'‐deoxyuridine (EdU) assay, colony formation assay, RNA‐sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells. Results Three metabolic subtypes (S1‐S3) with subtype‐specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune‐suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT‐rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype‐specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen‐activated protein kinase (MAPK) signaling. Conclusion Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.https://doi.org/10.1002/cac2.12513diacylglycerol kinase αintrahepatic cholangiocarcinomaMAPK signalingmetabolic classificationmultiomics analysisphosphatidic acid metabolism |
| spellingShingle | Weiren Liu Huqiang Wang Qianfu Zhao Chenyang Tao Weifeng Qu Yushan Hou Run Huang Zimei Sun Guiqi Zhu Xifei Jiang Yuan Fang Jun Gao Xiaoling Wu Zhixiang Yang Rongyu Ping Jiafeng Chen Rui Yang Tianhao Chu Jian Zhou Jia Fan Zheng Tang Dong Yang Yinghong Shi Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma Cancer Communications diacylglycerol kinase α intrahepatic cholangiocarcinoma MAPK signaling metabolic classification multiomics analysis phosphatidic acid metabolism |
| title | Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma |
| title_full | Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma |
| title_fullStr | Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma |
| title_full_unstemmed | Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma |
| title_short | Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma |
| title_sort | multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α dgka as a potential therapeutic target for intrahepatic cholangiocarcinoma |
| topic | diacylglycerol kinase α intrahepatic cholangiocarcinoma MAPK signaling metabolic classification multiomics analysis phosphatidic acid metabolism |
| url | https://doi.org/10.1002/cac2.12513 |
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