Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells
Abstract Background and aims Oncogenic KRAS mutations are present in approximately 90% of pancreatic ductal adenocarcinoma (PDAC). However, Kras mutation alone is insufficient to transform precancerous cells into metastatic PDAC. This study investigates how KRAS-mutated epithelial cells acquire the...
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| Format: | Article |
| Language: | English |
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BMC
2025-01-01
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| Series: | Molecular Cancer |
| Online Access: | https://doi.org/10.1186/s12943-024-02207-4 |
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| author | Chu-An Wang Ya-Chin Hou Yi-Kai Hong Yu-Jing Tai Chieh Shen Pei-Chi Hou Jhao-Lin Fu Cheng-Lin Wu Siao Muk Cheng Daw-Yang Hwang Yung-Yeh Su Yan-Shen Shan Shaw-Jenq Tsai |
| author_facet | Chu-An Wang Ya-Chin Hou Yi-Kai Hong Yu-Jing Tai Chieh Shen Pei-Chi Hou Jhao-Lin Fu Cheng-Lin Wu Siao Muk Cheng Daw-Yang Hwang Yung-Yeh Su Yan-Shen Shan Shaw-Jenq Tsai |
| author_sort | Chu-An Wang |
| collection | DOAJ |
| description | Abstract Background and aims Oncogenic KRAS mutations are present in approximately 90% of pancreatic ductal adenocarcinoma (PDAC). However, Kras mutation alone is insufficient to transform precancerous cells into metastatic PDAC. This study investigates how KRAS-mutated epithelial cells acquire the capacity to escape senescence or even immune clearance, thereby progressing to advanced PDAC. Methods Single-cell RNA sequencing and analysis of primary PDAC tumors were conducted. Genetically engineered pancreas-specific Kras-mutated, dual specificity phosphatase-2 (Dusp2) knockout mouse models were established. Human and mouse primary pancreatic cancer cell lines were used for in vitro assessment of cancer characteristics. Tumor progression was studied via pancreas orthotopic and portal vein injection in the immune-competent mice. Clinical relevance was validated by digital spatial transcriptomic analysis of PDAC tumors. Results Kras mutation induces the formation of pancreatic intraepithelial neoplasia (PanIN), these lesions also exhibit significant apoptotic signals. Single-cell RNA sequencing identified a subset of ERKactiveDUSP2low cells continuing to expand from early to advanced stage PDAC. In vitro and in vivo studies reveal that early infiltrating macrophage-derived tissue inhibitor of metallopeptidase 1 (TIMP-1) is the key factor in maintaining the ERKactiveDUSP2low cell population in a CD63-dependent manner. The ERKactiveDUSP2low cancer cells further exacerbate macrophage-mediated cancer malignancy, including loss of epithelial trait, increased lymphangiogenesis, and immune escape. Digital spatial profiling analysis of PDAC samples demonstrates the colocalization of TIMP-1high macrophages and CD63high cancer cells. The presence of TIMP-1high macrophages and CD63high epithelial cells correlates with poor prognosis in PDAC. Conclusions Our study reveals the vicious cycle between early infiltrating macrophages and pancreatic cancer cells, providing a mechanistic insight into the dynamic regulation directing pancreatic cancer progression. |
| format | Article |
| id | doaj-art-040a8b5047a74545852de832ff241143 |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-040a8b5047a74545852de832ff2411432025-01-19T12:12:38ZengBMCMolecular Cancer1476-45982025-01-0124111810.1186/s12943-024-02207-4Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cellsChu-An Wang0Ya-Chin Hou1Yi-Kai Hong2Yu-Jing Tai3Chieh Shen4Pei-Chi Hou5Jhao-Lin Fu6Cheng-Lin Wu7Siao Muk Cheng8Daw-Yang Hwang9Yung-Yeh Su10Yan-Shen Shan11Shaw-Jenq Tsai12Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityInstitute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityDepartment of Dermatology, Feinberg School of Medicine, Northwestern UniversityInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityDepartment of Physiology, College of Medicine, National Cheng Kung UniversityDepartment of Biochemistry and Molecular Genetics, University of Virginia School of MedicineInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityDepartment of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityNational Institute of Cancer Research, National Health Research InstitutesNational Institute of Cancer Research, National Health Research InstitutesNational Institute of Cancer Research, National Health Research InstitutesInstitute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityDepartment of Physiology, College of Medicine, National Cheng Kung UniversityAbstract Background and aims Oncogenic KRAS mutations are present in approximately 90% of pancreatic ductal adenocarcinoma (PDAC). However, Kras mutation alone is insufficient to transform precancerous cells into metastatic PDAC. This study investigates how KRAS-mutated epithelial cells acquire the capacity to escape senescence or even immune clearance, thereby progressing to advanced PDAC. Methods Single-cell RNA sequencing and analysis of primary PDAC tumors were conducted. Genetically engineered pancreas-specific Kras-mutated, dual specificity phosphatase-2 (Dusp2) knockout mouse models were established. Human and mouse primary pancreatic cancer cell lines were used for in vitro assessment of cancer characteristics. Tumor progression was studied via pancreas orthotopic and portal vein injection in the immune-competent mice. Clinical relevance was validated by digital spatial transcriptomic analysis of PDAC tumors. Results Kras mutation induces the formation of pancreatic intraepithelial neoplasia (PanIN), these lesions also exhibit significant apoptotic signals. Single-cell RNA sequencing identified a subset of ERKactiveDUSP2low cells continuing to expand from early to advanced stage PDAC. In vitro and in vivo studies reveal that early infiltrating macrophage-derived tissue inhibitor of metallopeptidase 1 (TIMP-1) is the key factor in maintaining the ERKactiveDUSP2low cell population in a CD63-dependent manner. The ERKactiveDUSP2low cancer cells further exacerbate macrophage-mediated cancer malignancy, including loss of epithelial trait, increased lymphangiogenesis, and immune escape. Digital spatial profiling analysis of PDAC samples demonstrates the colocalization of TIMP-1high macrophages and CD63high cancer cells. The presence of TIMP-1high macrophages and CD63high epithelial cells correlates with poor prognosis in PDAC. Conclusions Our study reveals the vicious cycle between early infiltrating macrophages and pancreatic cancer cells, providing a mechanistic insight into the dynamic regulation directing pancreatic cancer progression.https://doi.org/10.1186/s12943-024-02207-4 |
| spellingShingle | Chu-An Wang Ya-Chin Hou Yi-Kai Hong Yu-Jing Tai Chieh Shen Pei-Chi Hou Jhao-Lin Fu Cheng-Lin Wu Siao Muk Cheng Daw-Yang Hwang Yung-Yeh Su Yan-Shen Shan Shaw-Jenq Tsai Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells Molecular Cancer |
| title | Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells |
| title_full | Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells |
| title_fullStr | Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells |
| title_full_unstemmed | Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells |
| title_short | Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells |
| title_sort | intercellular timp 1 cd63 signaling directs the evolution of immune escape and metastasis in kras mutated pancreatic cancer cells |
| url | https://doi.org/10.1186/s12943-024-02207-4 |
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