Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer

Area of Science:

• Oncology
• Cancer Metabolism
• Epigenetics

Background:

• Metabolic reprogramming is crucial for cancer progression.
• The mechanisms sustaining triple-negative breast cancer (TNBC) growth despite low glycolysis are unclear.
• Pyruvate kinase M2 (PKM2) deficiency and impaired tumor glycolysis present a challenge in TNBC.

Purpose of the Study:

• To elucidate the metabolic adaptations enabling TNBC growth under glycolytic deficiency.
• To identify the molecular mechanisms linking PKM2, epigenetics, and metabolic switching in TNBC.
• To explore potential therapeutic strategies targeting TNBC's metabolic vulnerabilities.

Main Methods:

• Investigated metabolic pathways in TNBC cells with deficient glycolysis.
• Examined the interaction between PKM2 and EZH2.
• Analyzed the epigenetic regulation of the carnitine transporter SLC16A9.
• Assessed the impact of PKM2 inhibition on SLC16A9 expression and cellular metabolism.
• Evaluated the efficacy of dual targeting of EZH2 and FAO in TNBC models.

Main Results:

• TNBC cells switch from glycolysis to fatty acid β-oxidation (FAO) to sustain growth when glycolysis is deficient.
• PKM2 directly interacts with EZH2 to epigenetically silence the carnitine transporter SLC16A9.
• PKM2 inhibition disrupts EZH2 recruitment to SLC16A9, leading to its de-repression and increased carnitine influx.
• This metabolic reprogramming shifts TNBC cells towards an FAO-dependent, luminal-like state.
• Dual targeting of EZH2 and FAO demonstrated potent synthetic lethality in TNBC.

Conclusions:

• A novel metabolic switch from glycolysis to FAO fuels TNBC growth under glycolytic stress.
• The PKM2-EZH2-SLC16A9 axis mediates this metabolic adaptation and lineage plasticity.
• Targeting EZH2 and FAO concurrently offers a promising synthetic lethal strategy for TNBC treatment.