Single-cell and spatial-resolved profiling reveals cancer-associated fibroblast heterogeneity in colorectal cancer metabolic subtypes
Abstract Background Colorectal cancer (CRC) presents significant treatment challenges due to its high heterogeneity and complex intercellular interactions. Further exploration of CRC subtypes and interactions among tumor-specific clusters will facilitate the development of personalized treatment str...
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BMC
2025-02-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06103-3 |
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| author | Youpeng Wang Xingfeng Qiu Qinghai Li Jiale Qin Lvlan Ye Xiang Zhang Xingxiang Huang Xiangqiong Wen Ziyang Wang Weiling He Yuqin Di Qi Zhou |
| author_facet | Youpeng Wang Xingfeng Qiu Qinghai Li Jiale Qin Lvlan Ye Xiang Zhang Xingxiang Huang Xiangqiong Wen Ziyang Wang Weiling He Yuqin Di Qi Zhou |
| author_sort | Youpeng Wang |
| collection | DOAJ |
| description | Abstract Background Colorectal cancer (CRC) presents significant treatment challenges due to its high heterogeneity and complex intercellular interactions. Further exploration of CRC subtypes and interactions among tumor-specific clusters will facilitate the development of personalized treatment strategies. Methods Single-cell RNA sequencing and bulk RNA sequencing datasets were integrated to determine CRC metabolic subtypes by hierarchical clustering. The analysis was further extended to cellchat, pseudotime, immune infiltration, and clinicopathological relevance to explore the characteristics of secreted frizzled related protein 2 (SFRP2) + cancer-associated fibroblast (CAF) clusters, and validated by spatial transcriptomics (ST), in vivo experiments, and multiple immunohistochemistry (mIHC). Results CRC samples were stably classified into three heterogeneous metabolic subtypes, each exhibiting different microenvironment and CAF heterogeneity, particularly in the distribution of SFRP2 + CAF, which was aligned with metabolic activity. SFRP2 + CAF exhibits high extracellular matrix (ECM) activity and is closely involved in cellular communication, not only promoting the malignant progression of cancer cells but also inducing the differentiation of Tregs. Compared to responders of chemotherapy, the proportion of SFRP2 + CAFs is significantly increased in non-responders. Importantly, mIHC and ST analyses confirm that cancer cells with low expression of agmatinase (AGMAT) can recruit SFRP2 + CAFs, and Treg infiltration surrounding SFRP2 + CAFs was observed. AGMAT combined with oxaliplatin showed the best efficacy in vivo, which may be associated with the inhibition of SFRP2 + CAF infiltration. Conclusions Our study identified and described the potential protumor biological properties of SFRP2 + CAFs, and AGMAT may be a valuable target for disrupting their properties. |
| format | Article |
| id | doaj-art-e9f72ffe8bca421eb9020e0c2add3a10 |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-e9f72ffe8bca421eb9020e0c2add3a102025-08-20T03:00:58ZengBMCJournal of Translational Medicine1479-58762025-02-0123111810.1186/s12967-025-06103-3Single-cell and spatial-resolved profiling reveals cancer-associated fibroblast heterogeneity in colorectal cancer metabolic subtypesYoupeng Wang0Xingfeng Qiu1Qinghai Li2Jiale Qin3Lvlan Ye4Xiang Zhang5Xingxiang Huang6Xiangqiong Wen7Ziyang Wang8Weiling He9Yuqin Di10Qi Zhou11Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Gastrointestinal Surgery, School of Medicine, Xiang’an Hospital of Xiamen University, Xiamen UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Gastrointestinal Surgery, School of Medicine, Xiang’an Hospital of Xiamen University, Xiamen UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityCenter for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityCenter of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityAbstract Background Colorectal cancer (CRC) presents significant treatment challenges due to its high heterogeneity and complex intercellular interactions. Further exploration of CRC subtypes and interactions among tumor-specific clusters will facilitate the development of personalized treatment strategies. Methods Single-cell RNA sequencing and bulk RNA sequencing datasets were integrated to determine CRC metabolic subtypes by hierarchical clustering. The analysis was further extended to cellchat, pseudotime, immune infiltration, and clinicopathological relevance to explore the characteristics of secreted frizzled related protein 2 (SFRP2) + cancer-associated fibroblast (CAF) clusters, and validated by spatial transcriptomics (ST), in vivo experiments, and multiple immunohistochemistry (mIHC). Results CRC samples were stably classified into three heterogeneous metabolic subtypes, each exhibiting different microenvironment and CAF heterogeneity, particularly in the distribution of SFRP2 + CAF, which was aligned with metabolic activity. SFRP2 + CAF exhibits high extracellular matrix (ECM) activity and is closely involved in cellular communication, not only promoting the malignant progression of cancer cells but also inducing the differentiation of Tregs. Compared to responders of chemotherapy, the proportion of SFRP2 + CAFs is significantly increased in non-responders. Importantly, mIHC and ST analyses confirm that cancer cells with low expression of agmatinase (AGMAT) can recruit SFRP2 + CAFs, and Treg infiltration surrounding SFRP2 + CAFs was observed. AGMAT combined with oxaliplatin showed the best efficacy in vivo, which may be associated with the inhibition of SFRP2 + CAF infiltration. Conclusions Our study identified and described the potential protumor biological properties of SFRP2 + CAFs, and AGMAT may be a valuable target for disrupting their properties.https://doi.org/10.1186/s12967-025-06103-3Colorectal cancerSingle-cell RNA sequencingCancer-associated fibroblast (CAF)Chemoresistance |
| spellingShingle | Youpeng Wang Xingfeng Qiu Qinghai Li Jiale Qin Lvlan Ye Xiang Zhang Xingxiang Huang Xiangqiong Wen Ziyang Wang Weiling He Yuqin Di Qi Zhou Single-cell and spatial-resolved profiling reveals cancer-associated fibroblast heterogeneity in colorectal cancer metabolic subtypes Journal of Translational Medicine Colorectal cancer Single-cell RNA sequencing Cancer-associated fibroblast (CAF) Chemoresistance |
| title | Single-cell and spatial-resolved profiling reveals cancer-associated fibroblast heterogeneity in colorectal cancer metabolic subtypes |
| title_full | Single-cell and spatial-resolved profiling reveals cancer-associated fibroblast heterogeneity in colorectal cancer metabolic subtypes |
| title_fullStr | Single-cell and spatial-resolved profiling reveals cancer-associated fibroblast heterogeneity in colorectal cancer metabolic subtypes |
| title_full_unstemmed | Single-cell and spatial-resolved profiling reveals cancer-associated fibroblast heterogeneity in colorectal cancer metabolic subtypes |
| title_short | Single-cell and spatial-resolved profiling reveals cancer-associated fibroblast heterogeneity in colorectal cancer metabolic subtypes |
| title_sort | single cell and spatial resolved profiling reveals cancer associated fibroblast heterogeneity in colorectal cancer metabolic subtypes |
| topic | Colorectal cancer Single-cell RNA sequencing Cancer-associated fibroblast (CAF) Chemoresistance |
| url | https://doi.org/10.1186/s12967-025-06103-3 |
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