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

Wenxiao Yang1,2,3,4, Luo Hong1, Linwei Guo1,5

  • 1Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China.

Cell Discovery
|September 16, 2024
PubMed

Insights

Triple-negative breast cancer (TNBC) shows metabolic issues. Targeting SNRNP200, a splicing factor, disrupts tumor metabolism and improves immunotherapy by modulating T cells in glycolytic TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Metabolic dysregulation is a hallmark of triple-negative breast cancer (TNBC), presenting limited therapeutic options.
  • Splicing deregulation and spliceosome alterations are increasingly recognized in cancer progression.

Purpose of the Study:

  • To investigate the role of RNA splicing in metabolic reprogramming in TNBC.
  • To identify key splicing factors involved in glucose metabolism in TNBC.
  • To evaluate SNRNP200 as a therapeutic target for TNBC and its combination with immunotherapy.

Main Methods:

  • Multiomics data analysis from a TNBC cohort (n=465).
  • Investigated the mechanism of SNRNP200 regulation by glucose and its impact on metabolic gene splicing.
  • Utilized antisense oligonucleotide therapy targeting SNRNP200 in preclinical models.
  • Assessed the effects of SNRNP200 inhibition on tumor metabolism and anti-PD-1 therapy efficacy.
  • Correlated SNRNP200 levels with clinical response to immunotherapy.

Main Results:

  • Widespread splicing deregulation and increased spliceosome abundance were observed in the glycolytic TNBC subtype.
  • SNRNP200 was identified as a key mediator of glucose-driven metabolic reprogramming.
  • Glucose-induced acetylation of SNRNP200 K1610 prevents its degradation, leading to enhanced splicing of metabolic genes (GAPDH, ALDOA, GSS).
  • This results in increased lactic acid and glutathione production.
  • Targeting SNRNP200 with antisense oligonucleotides reduced tumor metabolism and potentiated anti-PD-1 therapy by modulating CD8+ T cells and regulatory T cells.
  • Higher SNRNP200 levels correlated with poorer immunotherapy response in glycolytic TNBC.

Conclusions:

  • RNA splicing and metabolic dysregulation are intricately linked in TNBC.
  • SNRNP200 is a critical regulator of cancer metabolism and a potential therapeutic target.
  • Combining SNRNP200 inhibition with anti-PD-1 immunotherapy offers a promising strategy for glycolytic TNBC.

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