Cross-cohort multi-omics analysis identifies novel clusters driven by EMT signatures in colorectal cancer
IntroductionThe pronounced heterogeneity of colorectal cancer (CRC) significantly impacts patient prognosis and therapeutic response, making elucidation of its molecular mechanisms critical for developing precision treatment strategies. This study aimed to systematically characterize tumor cell hete...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-06-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1628005/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849469801710223360 |
|---|---|
| author | Wu Ning Wenqing Jia Jingyuan Ning Lei Zhou Zongze Li Lin Zhang Xin Song |
| author_facet | Wu Ning Wenqing Jia Jingyuan Ning Lei Zhou Zongze Li Lin Zhang Xin Song |
| author_sort | Wu Ning |
| collection | DOAJ |
| description | IntroductionThe pronounced heterogeneity of colorectal cancer (CRC) significantly impacts patient prognosis and therapeutic response, making elucidation of its molecular mechanisms critical for developing precision treatment strategies. This study aimed to systematically characterize tumor cell heterogeneity and explore its clinical implications.MethodsFive single-cell RNA sequencing cohorts were integrated (comprising 70 CRC samples and 164,173 cells) to systematically analyze tumor cell heterogeneity. Unsupervised clustering analysis based on VEGFR+ tumor cell signature genes was used to stratify CRC patients. Key molecular mechanisms were validated through in vitro cellular experiments, in vivo animal models, molecular docking, and dynamics simulations.ResultsThe analysis successfully identified five distinct tumor cell subtypes, with the VEGFR+ subtype exhibiting marked epithelial-mesenchymal transition (EMT) activation signatures and strong association with metastasis and poor clinical outcomes. Based on VEGFR+ signature genes, CRC patients were stratified into three subgroups: C1 (metabolically active), C2 (proliferative), and C3 (invasive), with the C3 subtype demonstrating high metastatic potential, stem-like properties, and an immunosuppressive microenvironment, along with a five-year survival rate below 50%. Mechanistic investigations identified HOXC6 as a key driver of the C3 subtype, with HOXC6 knockout significantly suppressing CRC cell proliferation, migration, and invasion. Furthermore, molecular docking revealed that the targeted agent abemaciclib effectively binds HOXC6, with both cellular and animal experiments confirming its ability to inhibit CRC cell functions and significantly reduce tumor burden in nude mice.DiscussionThis study establishes the first single-cell-resolution molecular classification system for CRC, delineates the mechanistic link between EMT subtypes and metastatic progression, and identifies HOXC6 as a novel therapeutic vulnerability. These findings provide a translational foundation for precision oncology and offer new rationale for precision diagnosis and treatment of colorectal cancer. |
| format | Article |
| id | doaj-art-871dcc09b5ee43beb6a47c13a9e19175 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-871dcc09b5ee43beb6a47c13a9e191752025-08-20T03:25:20ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.16280051628005Cross-cohort multi-omics analysis identifies novel clusters driven by EMT signatures in colorectal cancerWu Ning0Wenqing Jia1Jingyuan Ning2Lei Zhou3Zongze Li4Lin Zhang5Xin Song6Department of General Surgery, China-Japan Friendship Hospital, Beijing, ChinaInstitute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, ChinaInstitute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of General Surgery, China-Japan Friendship Hospital, Beijing, ChinaDepartment of General Surgery, China-Japan Friendship Hospital, Beijing, ChinaDepartment of General Surgery, China-Japan Friendship Hospital, Beijing, ChinaDepartment of General Surgery, China-Japan Friendship Hospital, Beijing, ChinaIntroductionThe pronounced heterogeneity of colorectal cancer (CRC) significantly impacts patient prognosis and therapeutic response, making elucidation of its molecular mechanisms critical for developing precision treatment strategies. This study aimed to systematically characterize tumor cell heterogeneity and explore its clinical implications.MethodsFive single-cell RNA sequencing cohorts were integrated (comprising 70 CRC samples and 164,173 cells) to systematically analyze tumor cell heterogeneity. Unsupervised clustering analysis based on VEGFR+ tumor cell signature genes was used to stratify CRC patients. Key molecular mechanisms were validated through in vitro cellular experiments, in vivo animal models, molecular docking, and dynamics simulations.ResultsThe analysis successfully identified five distinct tumor cell subtypes, with the VEGFR+ subtype exhibiting marked epithelial-mesenchymal transition (EMT) activation signatures and strong association with metastasis and poor clinical outcomes. Based on VEGFR+ signature genes, CRC patients were stratified into three subgroups: C1 (metabolically active), C2 (proliferative), and C3 (invasive), with the C3 subtype demonstrating high metastatic potential, stem-like properties, and an immunosuppressive microenvironment, along with a five-year survival rate below 50%. Mechanistic investigations identified HOXC6 as a key driver of the C3 subtype, with HOXC6 knockout significantly suppressing CRC cell proliferation, migration, and invasion. Furthermore, molecular docking revealed that the targeted agent abemaciclib effectively binds HOXC6, with both cellular and animal experiments confirming its ability to inhibit CRC cell functions and significantly reduce tumor burden in nude mice.DiscussionThis study establishes the first single-cell-resolution molecular classification system for CRC, delineates the mechanistic link between EMT subtypes and metastatic progression, and identifies HOXC6 as a novel therapeutic vulnerability. These findings provide a translational foundation for precision oncology and offer new rationale for precision diagnosis and treatment of colorectal cancer.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1628005/fullcolorectal cancerEMTHOXC6scRNA-seqmetastatic |
| spellingShingle | Wu Ning Wenqing Jia Jingyuan Ning Lei Zhou Zongze Li Lin Zhang Xin Song Cross-cohort multi-omics analysis identifies novel clusters driven by EMT signatures in colorectal cancer Frontiers in Immunology colorectal cancer EMT HOXC6 scRNA-seq metastatic |
| title | Cross-cohort multi-omics analysis identifies novel clusters driven by EMT signatures in colorectal cancer |
| title_full | Cross-cohort multi-omics analysis identifies novel clusters driven by EMT signatures in colorectal cancer |
| title_fullStr | Cross-cohort multi-omics analysis identifies novel clusters driven by EMT signatures in colorectal cancer |
| title_full_unstemmed | Cross-cohort multi-omics analysis identifies novel clusters driven by EMT signatures in colorectal cancer |
| title_short | Cross-cohort multi-omics analysis identifies novel clusters driven by EMT signatures in colorectal cancer |
| title_sort | cross cohort multi omics analysis identifies novel clusters driven by emt signatures in colorectal cancer |
| topic | colorectal cancer EMT HOXC6 scRNA-seq metastatic |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1628005/full |
| work_keys_str_mv | AT wuning crosscohortmultiomicsanalysisidentifiesnovelclustersdrivenbyemtsignaturesincolorectalcancer AT wenqingjia crosscohortmultiomicsanalysisidentifiesnovelclustersdrivenbyemtsignaturesincolorectalcancer AT jingyuanning crosscohortmultiomicsanalysisidentifiesnovelclustersdrivenbyemtsignaturesincolorectalcancer AT leizhou crosscohortmultiomicsanalysisidentifiesnovelclustersdrivenbyemtsignaturesincolorectalcancer AT zongzeli crosscohortmultiomicsanalysisidentifiesnovelclustersdrivenbyemtsignaturesincolorectalcancer AT linzhang crosscohortmultiomicsanalysisidentifiesnovelclustersdrivenbyemtsignaturesincolorectalcancer AT xinsong crosscohortmultiomicsanalysisidentifiesnovelclustersdrivenbyemtsignaturesincolorectalcancer |