2. Academic Validation
  3. Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer

Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer

  • Cell Discov. 2024 Sep 17;10(1):96. doi: 10.1038/s41421-024-00715-7.
Wenxiao Yang # 1 2 3 4,  Luo Hong # 1,  Linwei Guo # 1 5,  Yunjin Wang 1,  Xiangchen Han 1 2 3 4,  Boyue Han 1 2 3 4,  Zheng Xing 1 6,  Guoliang Zhang 1,  Hongxia Zhou 1,  Chao Chen 1 2 3,  Hong Ling 2,  Zhimin Shao 1 2 3,  Xin Hu 7 8 9
Affiliations

Affiliations

  • 1 Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 2 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 3 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 4 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 5 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 6 Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 7 Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China. xinhu@fudan.edu.cn.
  • 8 Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. xinhu@fudan.edu.cn.
  • 9 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. xinhu@fudan.edu.cn.
  • # Contributed equally.
PMID: 39285160 DOI: 10.1038/s41421-024-00715-7
Abstract

Metabolic dysregulation is prominent in triple-negative breast Cancer (TNBC), yet therapeutic strategies targeting Cancer metabolism are limited. Here, utilizing multiomics data from our TNBC cohort (n = 465), we demonstrated widespread splicing deregulation and increased spliceosome abundance in the glycolytic TNBC subtype. We identified SNRNP200 as a crucial mediator of glucose-driven metabolic reprogramming. Mechanistically, glucose induces acetylation at SNRNP200 K1610, preventing its proteasomal degradation. Augmented SNRNP200 then facilitates splicing key metabolic enzyme-encoding genes (GAPDH, ALDOA, and GSS), leading to increased lactic acid and glutathione production. Targeting SNRNP200 with antisense oligonucleotide therapy impedes tumor metabolism and enhances the efficacy of anti-PD-1 therapy by activating intratumoral CD8+ T cells while suppressing regulatory T cells. Clinically, higher SNRNP200 levels indicate an inferior response to immunotherapy in glycolytic TNBCs. Overall, our study revealed the intricate interplay between RNA splicing and metabolic dysregulation, suggesting an innovative combination strategy for immunotherapy in glycolytic TNBCs.

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