Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation

Area of Science:

• Molecular Biology
• Cancer Biology
• Metabolic Pathways

Background:

• Cancer-associated mutations in SF3B1 lead to aberrant mRNA splicing.
• The biological and therapeutic consequences of this missplicing are not well understood.

Purpose of the Study:

• To investigate the downstream effects of SF3B1 mutations on cellular processes.
• To identify potential therapeutic vulnerabilities associated with SF3B1 mutations.

Main Methods:

• Analysis of transcriptome, proteome, and metabolome in human cells with mutant SF3B1.
• In vitro and in vivo studies assessing the impact of serine and glycine deprivation on cancer cell growth and tumor xenografts.

Main Results:

• Mutant SF3B1 altered cellular metabolism, decreasing mitochondrial respiration and suppressing the serine synthesis pathway.
• SF3B1 mutations induced a vulnerability to serine deprivation, mediated by downregulation of PHGDH.
• Dietary restriction of serine and glycine inhibited the growth of SF3B1-mutant xenografts in mice.

Conclusions:

• SF3B1 mutations play a role in altered energy metabolism in cancer.
• Targeting serine metabolism presents a potential therapeutic strategy for SF3B1-mutant cancers.