RAB3B Dictates mTORC1/S6 Signaling in Chordoma and Predicts Response to mTORC1-Targeted Therapy.

in Advanced science (Weinheim, Baden-Wurttemberg, Germany) by 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

TLDR

  • The study identifies RAB3B as a key oncogenic regulator in chordoma and suggests that targeting the mTORC1 pathway may be an effective therapeutic approach.

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.

Overview

  • The study aimed to uncover the tumorigenic regulatory mechanisms of chordoma, a rare and aggressive form of cancer.
  • The researchers used transcriptome and proteome analyses to identify RAB3B as a key oncogenic regulator in chordoma, which has high expression and enhancer-associated transcriptional activity.
  • The study explored the role of RAB3B in chordoma tumorigenicity, stemness, and response to treatment, and its relationship with the mTORC1 pathway.

Comparative Analysis & Findings

  • RAB3B knockout attenuated the stemness and malignant biological properties of chordoma cells in vivo and in vitro.
  • Pharmacological targeting of the mTORC1 pathway inhibited RAB3B-induced stemness regulation, protein translation, and chordoma tumorigenicity.
  • RAB3B knockdown desensitized mTORC1 inhibition, and the combination of RAB3B and p-S6 suggested a good prognostic value and predicted mTORC1 inhibitors response for chordoma patients.

Implications and Future Directions

  • The study provides novel insights into the regulatory mechanisms of chordoma and identifies RAB3B and DUSP12 as potential therapeutic targets.
  • Further research is needed to explore the detailed mechanisms of RAB3B-mediated S6 phosphorylation and its implications for chordoma development and progression.
  • The study suggests that mTORC1-targeted therapy may be an effective treatment approach for advanced chordoma patients with aberrant RAB3B/p-S6 hyperactivation.
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