Discoidin domain receptor inhibitor DDR1-IN-1 induces autophagy and necroptotic cell death in malignant peripheral nerve sheath tumor
Abstract Malignant peripheral nerve sheath tumor (MPNST) is a soft tissue sarcoma commonly associated with the tumor-predisposition disorder neurofibromatosis 1. The extracellular matrix collagens contribute to many fibrotic tumors; however, the role of collagen signaling in MPNST was unclear. This...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-03-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02367-2 |
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| author | Guan-Yi Lai Yu-Cheng Lee Hao-Jui Weng Kuei-Hung Lai Min-Chen Hsiang Kai-Yu Hsu Chung-Ping Liao |
| author_facet | Guan-Yi Lai Yu-Cheng Lee Hao-Jui Weng Kuei-Hung Lai Min-Chen Hsiang Kai-Yu Hsu Chung-Ping Liao |
| author_sort | Guan-Yi Lai |
| collection | DOAJ |
| description | Abstract Malignant peripheral nerve sheath tumor (MPNST) is a soft tissue sarcoma commonly associated with the tumor-predisposition disorder neurofibromatosis 1. The extracellular matrix collagens contribute to many fibrotic tumors; however, the role of collagen signaling in MPNST was unclear. This study investigated the effects of blocking the interaction between collagens and their receptors in MPNST. We first analyzed the expressions of collagen family proteins in MPNSTs and found an overall increase compared to neurofibroma. Treatment of DDR1-IN-1, a small molecule inhibitor for the collagen receptor discoidin domain receptor, induced a robust MPNST cell death, highlighting the dependence of MPNST survival on collagen signaling. DDR1-IN-1 induced MPNST cell death by activating autophagy and necroptosis signaling. Treatment of necroptosis inhibitors necrostatin-1 or necrosulfonamide reduced the numbers of DDR1-IN-1-induced necrotic cells and autolysosomes, suggesting that the autophagic process depends on necroptosis activation. Combinations of DDR1-IN-1 with other anti-MPNST agents revealed synergistic activities against MPNST. In summary, this study discovered a critical MPNST death signaling induced by the small molecule DDR1-IN-1, which might shed light on future MPNST therapeutic strategies. |
| format | Article |
| id | doaj-art-0da8f0dae4824952adf2f3ab5ef980db |
| institution | OA Journals |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-0da8f0dae4824952adf2f3ab5ef980db2025-08-20T02:16:44ZengNature Publishing GroupCell Death Discovery2058-77162025-03-0111111210.1038/s41420-025-02367-2Discoidin domain receptor inhibitor DDR1-IN-1 induces autophagy and necroptotic cell death in malignant peripheral nerve sheath tumorGuan-Yi Lai0Yu-Cheng Lee1Hao-Jui Weng2Kuei-Hung Lai3Min-Chen Hsiang4Kai-Yu Hsu5Chung-Ping Liao6Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityGraduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityAbstract Malignant peripheral nerve sheath tumor (MPNST) is a soft tissue sarcoma commonly associated with the tumor-predisposition disorder neurofibromatosis 1. The extracellular matrix collagens contribute to many fibrotic tumors; however, the role of collagen signaling in MPNST was unclear. This study investigated the effects of blocking the interaction between collagens and their receptors in MPNST. We first analyzed the expressions of collagen family proteins in MPNSTs and found an overall increase compared to neurofibroma. Treatment of DDR1-IN-1, a small molecule inhibitor for the collagen receptor discoidin domain receptor, induced a robust MPNST cell death, highlighting the dependence of MPNST survival on collagen signaling. DDR1-IN-1 induced MPNST cell death by activating autophagy and necroptosis signaling. Treatment of necroptosis inhibitors necrostatin-1 or necrosulfonamide reduced the numbers of DDR1-IN-1-induced necrotic cells and autolysosomes, suggesting that the autophagic process depends on necroptosis activation. Combinations of DDR1-IN-1 with other anti-MPNST agents revealed synergistic activities against MPNST. In summary, this study discovered a critical MPNST death signaling induced by the small molecule DDR1-IN-1, which might shed light on future MPNST therapeutic strategies.https://doi.org/10.1038/s41420-025-02367-2 |
| spellingShingle | Guan-Yi Lai Yu-Cheng Lee Hao-Jui Weng Kuei-Hung Lai Min-Chen Hsiang Kai-Yu Hsu Chung-Ping Liao Discoidin domain receptor inhibitor DDR1-IN-1 induces autophagy and necroptotic cell death in malignant peripheral nerve sheath tumor Cell Death Discovery |
| title | Discoidin domain receptor inhibitor DDR1-IN-1 induces autophagy and necroptotic cell death in malignant peripheral nerve sheath tumor |
| title_full | Discoidin domain receptor inhibitor DDR1-IN-1 induces autophagy and necroptotic cell death in malignant peripheral nerve sheath tumor |
| title_fullStr | Discoidin domain receptor inhibitor DDR1-IN-1 induces autophagy and necroptotic cell death in malignant peripheral nerve sheath tumor |
| title_full_unstemmed | Discoidin domain receptor inhibitor DDR1-IN-1 induces autophagy and necroptotic cell death in malignant peripheral nerve sheath tumor |
| title_short | Discoidin domain receptor inhibitor DDR1-IN-1 induces autophagy and necroptotic cell death in malignant peripheral nerve sheath tumor |
| title_sort | discoidin domain receptor inhibitor ddr1 in 1 induces autophagy and necroptotic cell death in malignant peripheral nerve sheath tumor |
| url | https://doi.org/10.1038/s41420-025-02367-2 |
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