Inhibition of CDH11 Activates cGAS‐STING by Stimulating Branched Chain Amino Acid Catabolism and Mitigates Lung Metastasis of Adenoid Cystic Carcinoma
Abstract Salivary adenoid cystic carcinoma (SACC) is an intractable malignant tumor originates in the secretory glands and frequently metastasizes to the lungs. Hybrid epithelial‐mesenchymal transition (EMT) cells within the tumors are correlated with augmented proliferative capacity and facilitatio...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202408751 |
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| author | Rui‐Feng Li Shuo Liu Qian Gao Min Fu Xin‐Yi Sun Mian Xiao Xi‐Yuan Ge Xin Peng |
| author_facet | Rui‐Feng Li Shuo Liu Qian Gao Min Fu Xin‐Yi Sun Mian Xiao Xi‐Yuan Ge Xin Peng |
| author_sort | Rui‐Feng Li |
| collection | DOAJ |
| description | Abstract Salivary adenoid cystic carcinoma (SACC) is an intractable malignant tumor originates in the secretory glands and frequently metastasizes to the lungs. Hybrid epithelial‐mesenchymal transition (EMT) cells within the tumors are correlated with augmented proliferative capacity and facilitation of lung metastasis. Single‐cell RNA sequencing and spatial transcriptomic sequencing are employed to reveal the hybrid EMT subsets within the vascular fibroblast microenvironment. These hybrid EMT cells exhibit a pro‐tumorigenic impact in vitro. Notably, cadherin 11 (CDH11), a specific marker for hybrid EMT cells, may exert its regulatory role in cellular function by interfering with branched‐chain amino acids (BCAA) metabolism by inhibiting branched‐chain ketoacid dehydrogenase to activate the mammalian target of the rapamycin pathway, thus making it a potential therapeutic target for SACC. Furthermore, celecoxib and its derivatives are specific CDH11 inhibitors that regulate BCAA metabolism, increase reactive oxygen species production, and subsequently activate the cyclic GMP‐AMP synthase‐stimulator of the interferongene pathway (cGAS‐STING). They also inhibit lung metastasis in NOD‐SCID mice in vivo. Overall, these findings suggest a promising treatment strategy that targets hybrid EMT cells to mitigate lung metastasis in SACC. Celecoxib may serve as a promising clinical intervention for the treatment of lung metastases in patients with SACC. |
| format | Article |
| id | doaj-art-f0fa0295a2c84608b6116a93bc36be7d |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-f0fa0295a2c84608b6116a93bc36be7d2025-08-20T01:51:48ZengWileyAdvanced Science2198-38442025-02-01128n/an/a10.1002/advs.202408751Inhibition of CDH11 Activates cGAS‐STING by Stimulating Branched Chain Amino Acid Catabolism and Mitigates Lung Metastasis of Adenoid Cystic CarcinomaRui‐Feng Li0Shuo Liu1Qian Gao2Min Fu3Xin‐Yi Sun4Mian Xiao5Xi‐Yuan Ge6Xin Peng7Department of Oral and Maxillofacial Surgery Peking University School and Hospital of Stomatology Beijing 100081 P. R. ChinaDepartment of Oral and Maxillofacial Surgery Peking University School and Hospital of Stomatology Beijing 100081 P. R. ChinaDepartment of Oral and Maxillofacial Surgery Peking University School and Hospital of Stomatology Beijing 100081 P. R. ChinaDepartment of Oral and Maxillofacial Surgery Peking University School and Hospital of Stomatology Beijing 100081 P. R. ChinaDepartment of Oral and Maxillofacial Surgery Peking University School and Hospital of Stomatology Beijing 100081 P. R. ChinaDepartment of Oral and Maxillofacial Surgery Peking University School and Hospital of Stomatology Beijing 100081 P. R. ChinaDepartment of Oral and Maxillofacial Surgery Peking University School and Hospital of Stomatology Beijing 100081 P. R. ChinaDepartment of Oral and Maxillofacial Surgery Peking University School and Hospital of Stomatology Beijing 100081 P. R. ChinaAbstract Salivary adenoid cystic carcinoma (SACC) is an intractable malignant tumor originates in the secretory glands and frequently metastasizes to the lungs. Hybrid epithelial‐mesenchymal transition (EMT) cells within the tumors are correlated with augmented proliferative capacity and facilitation of lung metastasis. Single‐cell RNA sequencing and spatial transcriptomic sequencing are employed to reveal the hybrid EMT subsets within the vascular fibroblast microenvironment. These hybrid EMT cells exhibit a pro‐tumorigenic impact in vitro. Notably, cadherin 11 (CDH11), a specific marker for hybrid EMT cells, may exert its regulatory role in cellular function by interfering with branched‐chain amino acids (BCAA) metabolism by inhibiting branched‐chain ketoacid dehydrogenase to activate the mammalian target of the rapamycin pathway, thus making it a potential therapeutic target for SACC. Furthermore, celecoxib and its derivatives are specific CDH11 inhibitors that regulate BCAA metabolism, increase reactive oxygen species production, and subsequently activate the cyclic GMP‐AMP synthase‐stimulator of the interferongene pathway (cGAS‐STING). They also inhibit lung metastasis in NOD‐SCID mice in vivo. Overall, these findings suggest a promising treatment strategy that targets hybrid EMT cells to mitigate lung metastasis in SACC. Celecoxib may serve as a promising clinical intervention for the treatment of lung metastases in patients with SACC.https://doi.org/10.1002/advs.202408751adenoid cystic carcinomacelecoxibhybrid epithelial‐mesenchymal transforming cellsspatial transcriptome sequencingsingle‐cell transcriptome sequencingtargeted therapy |
| spellingShingle | Rui‐Feng Li Shuo Liu Qian Gao Min Fu Xin‐Yi Sun Mian Xiao Xi‐Yuan Ge Xin Peng Inhibition of CDH11 Activates cGAS‐STING by Stimulating Branched Chain Amino Acid Catabolism and Mitigates Lung Metastasis of Adenoid Cystic Carcinoma Advanced Science adenoid cystic carcinoma celecoxib hybrid epithelial‐mesenchymal transforming cells spatial transcriptome sequencing single‐cell transcriptome sequencing targeted therapy |
| title | Inhibition of CDH11 Activates cGAS‐STING by Stimulating Branched Chain Amino Acid Catabolism and Mitigates Lung Metastasis of Adenoid Cystic Carcinoma |
| title_full | Inhibition of CDH11 Activates cGAS‐STING by Stimulating Branched Chain Amino Acid Catabolism and Mitigates Lung Metastasis of Adenoid Cystic Carcinoma |
| title_fullStr | Inhibition of CDH11 Activates cGAS‐STING by Stimulating Branched Chain Amino Acid Catabolism and Mitigates Lung Metastasis of Adenoid Cystic Carcinoma |
| title_full_unstemmed | Inhibition of CDH11 Activates cGAS‐STING by Stimulating Branched Chain Amino Acid Catabolism and Mitigates Lung Metastasis of Adenoid Cystic Carcinoma |
| title_short | Inhibition of CDH11 Activates cGAS‐STING by Stimulating Branched Chain Amino Acid Catabolism and Mitigates Lung Metastasis of Adenoid Cystic Carcinoma |
| title_sort | inhibition of cdh11 activates cgas sting by stimulating branched chain amino acid catabolism and mitigates lung metastasis of adenoid cystic carcinoma |
| topic | adenoid cystic carcinoma celecoxib hybrid epithelial‐mesenchymal transforming cells spatial transcriptome sequencing single‐cell transcriptome sequencing targeted therapy |
| url | https://doi.org/10.1002/advs.202408751 |
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