RAB3B Dictates mTORC1/S6 Signaling in Chordoma and Predicts Response to mTORC1‐Targeted Therapy
Abstract Chordoma, a rare mesenchymal malignancy, exhibits a high tendency to postoperative recurrence and poor prognosis. To date, its tumorigenic regulatory mechanisms remain elusive, leading to a lack of effective therapeutic targets and drug sensitivity indicators. Here, via transcriptome and pr...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202415384 |
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| author | Jianxuan Gao Jiali Jin Runzhi Huang Siqiao Wang Sihui Song Yu Zhang Yongai Li Jun Lin Zhengyan Chang Zongqiang Huang Wei Sun Huabin Yin Dianwen Song Jianru Xiao Ping Wang Tong Meng |
| author_facet | Jianxuan Gao Jiali Jin Runzhi Huang Siqiao Wang Sihui Song Yu Zhang Yongai Li Jun Lin Zhengyan Chang Zongqiang Huang Wei Sun Huabin Yin Dianwen Song Jianru Xiao Ping Wang Tong Meng |
| author_sort | Jianxuan Gao |
| collection | DOAJ |
| description | Abstract Chordoma, a rare mesenchymal malignancy, exhibits a high tendency to postoperative recurrence and poor prognosis. To date, its tumorigenic regulatory mechanisms remain elusive, leading to a lack of effective therapeutic targets and drug sensitivity indicators. Here, via transcriptome and proteome analyses, RAB3B is unveiled as a prominent oncogenic regulator in chordoma, with high expression and enhancer‐associated transcriptional activity. Notably, RAB3B ablation attenuated the chordoma cell stemness and malignant biological properties in vivo and in vitro. Through determining the RAB3B‐mediated program in chordoma, it is identified that it enhanced the phosphorylation of S6 specifically at S235/236 and directly bound to S6. Mechanistically, RAB3B physically interacted with phosphorylase DUSP12, and blocked the DUSP12‐mediated dephosphorylation of p‐S6 (S235/236). Pharmacological targeting mTORC1 pathway dramatically impeded the RAB3B‐induced stemness regulation, protein translation, and chordoma tumorigenicity, while RAB3B knockdown desensitized mTORC1 inhibition. In clinic, the combination of RAB3B and p‐S6 suggested a good prognostic value and predicted mTORC1 inhibitors response for chordoma patients. Altogether, this work uncovers RAB3B/DUSP12 as the novel regulators of S6 phosphorylation (S235/236), and suggests the oncogenic and predictive roles of RAB3B/p‐S6 in chordoma, indicating therapeutic potentials of mTORC1‐targeted therapy for advanced chordoma patients with aberrant RAB3B/p‐S6 hyperactivation. |
| format | Article |
| id | doaj-art-4e41662737db429bb019fd6a3b3bb19f |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-4e41662737db429bb019fd6a3b3bb19f2025-08-20T02:26:18ZengWileyAdvanced Science2198-38442025-05-011219n/an/a10.1002/advs.202415384RAB3B Dictates mTORC1/S6 Signaling in Chordoma and Predicts Response to mTORC1‐Targeted TherapyJianxuan Gao0Jiali Jin1Runzhi Huang2Siqiao Wang3Sihui Song4Yu Zhang5Yongai Li6Jun Lin7Zhengyan Chang8Zongqiang Huang9Wei Sun10Huabin Yin11Dianwen Song12Jianru Xiao13Ping Wang14Tong Meng15Department of Orthopedics Shanghai Bone Tumor Institute Shanghai General Hospital School of Medicine Shanghai Jiaotong University Shanghai 201620 P. R. ChinaTongji University Cancer Center Shanghai Tenth People's Hospital School of Medicine Tongji University Shanghai 200072 P. R. ChinaDepartment of Orthopedics Tongji Hospital School of Medicine Tongji University Shanghai 200065 P. R. ChinaDepartment of Orthopedics Tongji Hospital School of Medicine Tongji University Shanghai 200065 P. R. ChinaTongji University Cancer Center Shanghai Tenth People's Hospital School of Medicine Tongji University Shanghai 200072 P. R. ChinaTongji University Cancer Center Shanghai Tenth People's Hospital School of Medicine Tongji University Shanghai 200072 P. R. ChinaDepartment of Orthopedics Shanghai Bone Tumor Institute Shanghai General Hospital School of Medicine Shanghai Jiaotong University Shanghai 201620 P. R. ChinaDepartment of Pathology Shanghai General Hospital School of Medicine Shanghai Jiaotong University Shanghai 201620 P. R. ChinaDepartment of Pathology Shanghai Tenth People's Hospital School of Medicine Tongji University Shanghai 200072 P. R. ChinaDepartment of Orthopedics The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 P. R. ChinaDepartment of Orthopedics Shanghai Bone Tumor Institute Shanghai General Hospital School of Medicine Shanghai Jiaotong University Shanghai 201620 P. R. ChinaDepartment of Orthopedics Shanghai Bone Tumor Institute Shanghai General Hospital School of Medicine Shanghai Jiaotong University Shanghai 201620 P. R. ChinaDepartment of Orthopedics Shanghai Bone Tumor Institute Shanghai General Hospital School of Medicine Shanghai Jiaotong University Shanghai 201620 P. R. ChinaDepartment of Orthopedics Oncology Changzheng Hospital Navy Medical University Shanghai 200003 P. R. ChinaTongji University Cancer Center Shanghai Tenth People's Hospital School of Medicine Tongji University Shanghai 200072 P. R. ChinaDepartment of Orthopedics Shanghai Bone Tumor Institute Shanghai General Hospital School of Medicine Shanghai Jiaotong University Shanghai 201620 P. R. ChinaAbstract Chordoma, a rare mesenchymal malignancy, exhibits a high tendency to postoperative recurrence and poor prognosis. To date, its tumorigenic regulatory mechanisms remain elusive, leading to a lack of effective therapeutic targets and drug sensitivity indicators. Here, via transcriptome and proteome analyses, RAB3B is unveiled as a prominent oncogenic regulator in chordoma, with high expression and enhancer‐associated transcriptional activity. Notably, RAB3B ablation attenuated the chordoma cell stemness and malignant biological properties in vivo and in vitro. Through determining the RAB3B‐mediated program in chordoma, it is identified that it enhanced the phosphorylation of S6 specifically at S235/236 and directly bound to S6. Mechanistically, RAB3B physically interacted with phosphorylase DUSP12, and blocked the DUSP12‐mediated dephosphorylation of p‐S6 (S235/236). Pharmacological targeting mTORC1 pathway dramatically impeded the RAB3B‐induced stemness regulation, protein translation, and chordoma tumorigenicity, while RAB3B knockdown desensitized mTORC1 inhibition. In clinic, the combination of RAB3B and p‐S6 suggested a good prognostic value and predicted mTORC1 inhibitors response for chordoma patients. Altogether, this work uncovers RAB3B/DUSP12 as the novel regulators of S6 phosphorylation (S235/236), and suggests the oncogenic and predictive roles of RAB3B/p‐S6 in chordoma, indicating therapeutic potentials of mTORC1‐targeted therapy for advanced chordoma patients with aberrant RAB3B/p‐S6 hyperactivation.https://doi.org/10.1002/advs.202415384chordomaDUSP12mTORC1 signalingRAB3Btargeted therapy |
| spellingShingle | Jianxuan Gao Jiali Jin Runzhi Huang Siqiao Wang Sihui Song Yu Zhang Yongai Li Jun Lin Zhengyan Chang Zongqiang Huang Wei Sun Huabin Yin Dianwen Song Jianru Xiao Ping Wang Tong Meng RAB3B Dictates mTORC1/S6 Signaling in Chordoma and Predicts Response to mTORC1‐Targeted Therapy Advanced Science chordoma DUSP12 mTORC1 signaling RAB3B targeted therapy |
| title | RAB3B Dictates mTORC1/S6 Signaling in Chordoma and Predicts Response to mTORC1‐Targeted Therapy |
| title_full | RAB3B Dictates mTORC1/S6 Signaling in Chordoma and Predicts Response to mTORC1‐Targeted Therapy |
| title_fullStr | RAB3B Dictates mTORC1/S6 Signaling in Chordoma and Predicts Response to mTORC1‐Targeted Therapy |
| title_full_unstemmed | RAB3B Dictates mTORC1/S6 Signaling in Chordoma and Predicts Response to mTORC1‐Targeted Therapy |
| title_short | RAB3B Dictates mTORC1/S6 Signaling in Chordoma and Predicts Response to mTORC1‐Targeted Therapy |
| title_sort | rab3b dictates mtorc1 s6 signaling in chordoma and predicts response to mtorc1 targeted therapy |
| topic | chordoma DUSP12 mTORC1 signaling RAB3B targeted therapy |
| url | https://doi.org/10.1002/advs.202415384 |
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