Proteogenomic Characterization Reveals Metabolic Vulnerabilities and Aberrant Phosphorylation in Colorectal Metastasis to Liver
文献类型：期刊论文
| 作者 | Zhao, Wensi1,8; Zhao, Lei1,8; Lian, Yannan7; Liu, Zhiwei9; Li, Yaqi10; Wang, Xuege7; Zhang, Mingya9; Li, Ni7; Guo, Jingli9; Shen, Danqing11 |
| 刊名 | ADVANCED SCIENCE
 |
| 出版日期 | 2025-11-06 |
| 页码 | 17 |
| 关键词 | biomarker colorectal liver metastasis phosphoproteomics proteomic subtype proteomics SHMT1 |
| DOI | 10.1002/advs.202511744 |
| 英文摘要 | Colorectal liver metastasis (CRLM) is one of the leading death causes among colorectal cancer (CRC) patients, yet its underlying molecular events remain poorly understood, particularly at the proteomic and phosphoproteomic levels. A proteogenomic analysis combining genomics, transcriptomics, proteomics, and phosphoproteomics is performed on 102 samples from 34 treatment-na & iuml;ve CRLM patients, including primary CRC, adjacent normal colorectal, and matched liver metastasis tissues. CRC cell lines, organoids, mouse models, and an independent patient cohort are used to validate the findings. Proteomics and phosphoproteomics show profoundly dysregulated pathways in liver metastasis tissues, notably disruptions in carbon metabolism. Functional validation using CRC organoids and mouse models demonstrates that the one-carbon metabolism enzyme SHMT1 promotes CRC tumorigenesis and metastasis via formate-mediated AMPK inhibition, whereas PIM kinase-dependent NDRG1 Ser330 phosphorylation exacerbates liver metastasis by promoting ubiquitin-dependent degradation of NDRG1. Unsupervised clustering identifies two proteomic subtypes of liver metastasis samples with distinct clinical outcomes: a poor-prognosis C1 (metabolism) subtype and a better-prognosis C2 (RNA function) subtype. Considering expression frequency, specificity, and functional relevance, FTCD, GPD1, SOD2, and EIF4B Ser422 phosphorylation are further identified and validated as subtype prognostic biomarkers. This study provides critical insights into the molecular mechanisms underlying CRLM and offers resources for high-risk metastatic CRC. |
| WOS关键词 | HUMAN COLON ; CANCER ; NDRG1 ; PROGRESSION ; RECURRENCE ; CARCINOMA ; RESECTION ; PROTEIN ; MARKER |
| 资助项目 | Guangdong High-level New RD Institute[2019B090904008] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830000] ; Innovative Research Team of High-Level Local Universities in Shanghai[SHSMU-ZDCX20212700] ; Guangdong High-level Innovative Research Institute[2021B0909050003] ; National Natural Science Foundation of China[22225702] ; National Natural Science Foundation of China[T2488301] ; National Natural Science Foundation of China[U24A20524] ; National Natural Science Foundation of China[82372974] ; National Natural Science Foundation of China[82473500] ; National Natural Science Foundation of China[8245103] ; Jinfeng startup funding in Chongqing ; Zhongshan Science and Technology Bureau[CXTD2023009] |
| WOS研究方向 | Chemistry ; Science & Technology - Other Topics ; Materials Science |
| 语种 | 英语 |
| WOS记录号 | WOS:001608556100001 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/319753]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Peng, Junjie; Qin, Jun; Tan, Minjia |
| 作者单位 | 1.Tongji Univ, Canc Ctr, Sch Med, Shanghai 200434, Peoples R China 2.Fudan Univ, Sch Comp Sci & Technol, Shanghai Key Lab Intelligent Informat Proc, Shanghai 200433, Peoples R China 3.Sungkyunkwan Univ, Sch Pharm, Suwon 16419, South Korea 4.Jiangsu Ocean Univ, Coll Pharm, Jiangsu Key Lab Marine Pharmaceut Cpd Screening, Lianyungang 222005, Peoples R China 5.Jinfeng Lab, Chongqing 401329, Peoples R China 6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, 320 Yueyang Rd, Shanghai 200031, Peoples R China 8.Tongji Univ, Shanghai Peoples Hosp 4, Translat Res Inst Brain & Brain Like Intelligence, Sch Med, Shanghai 200434, Peoples R China 9.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 10.Fudan Univ, Shanghai Canc Ctr, Shanghai Med Coll, Dept Colorectal Surg,Dept Oncol, Shanghai 200032, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhao, Wensi,Zhao, Lei,Lian, Yannan,et al. Proteogenomic Characterization Reveals Metabolic Vulnerabilities and Aberrant Phosphorylation in Colorectal Metastasis to Liver[J]. ADVANCED SCIENCE,2025:17. |
| APA | Zhao, Wensi.,Zhao, Lei.,Lian, Yannan.,Liu, Zhiwei.,Li, Yaqi.,...&Tan, Minjia.(2025).Proteogenomic Characterization Reveals Metabolic Vulnerabilities and Aberrant Phosphorylation in Colorectal Metastasis to Liver.ADVANCED SCIENCE,17. |
| MLA | Zhao, Wensi,et al."Proteogenomic Characterization Reveals Metabolic Vulnerabilities and Aberrant Phosphorylation in Colorectal Metastasis to Liver".ADVANCED SCIENCE (2025):17. |
入库方式： OAI收割
来源：上海药物研究所
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