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LSD1-GLS2 axis drives subtype-specific chemoresistance in pancreatic cancer through glutaminolysis reprogramming
Zhefang Wang1,2, Qiu Huang1, Jiangang Zhao1
1Department of General, Visceral, Thoracic and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy due to its aggressive biology and therapeutic resistance. Lysine-specific demethylase 1 (LSD1), an epigenetic regulator, is overexpressed in PDAC and linked to poor prognosis, yet its context-dependent roles in metabolic subtypes and chemoresistance remain undefined. Here, we show that LSD1 knockdown has opposing, subtype-specific effects on chemotherapeutic responses: it sensitized RSK-subtype cells (L3.6pl, PANC-1) to chemotherapy but induced resistance in KRAS-subtype cells (BxPC-3, TBO368). Integrated analyses revealed mitochondrial dysfunction and defective mitophagy as hallmarks distinguishing KRAS- from RSK-subtype PDAC. Critically, mitochondrial targeting through respiratory modulation or mitophagy manipulation overrides LSD1-mediated subtype-specific chemoresistance, establishing mitochondrial fitness as the mechanistic determinant. Mechanistically, LSD1 transcriptionally regulates GLS2 to drive glutamine metabolic reprogramming, promoting reductive carboxylation in KRAS-subtype cells and oxidative metabolism in RSK-subtype cells. Our work establishes the LSD1-GLS2 axis as a metabolic switch controlling PDAC chemosensitivity and provides a framework for subtype-specific therapeutic strategies.
Insights
Lysine-specific demethylase 1 (LSD1) impacts pancreatic cancer treatment differently based on subtype. Targeting mitochondria can overcome LSD1-driven chemoresistance in specific pancreatic ductal adenocarcinoma (PDAC) subtypes.
Area of Science:
- Oncology
- Epigenetics
- Metabolic pathways
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with poor therapeutic outcomes.
- Lysine-specific demethylase 1 (LSD1), an epigenetic regulator, is overexpressed in PDAC and associated with poor prognosis.
- The specific roles of LSD1 in PDAC metabolic subtypes and chemoresistance are not fully understood.
Purpose of the Study:
- To investigate the context-dependent functions of LSD1 in different PDAC subtypes.
- To elucidate the mechanisms underlying LSD1-mediated chemoresistance.
- To identify potential therapeutic strategies targeting metabolic vulnerabilities in PDAC.
Main Methods:
- LSD1 knockdown experiments in distinct PDAC cell lines (RSK-subtype and KRAS-subtype).
- Analysis of mitochondrial function, mitophagy, and metabolic reprogramming (glutaminolysis).
- Assessment of chemotherapeutic responses and manipulation of mitochondrial activity.
Main Results:
- LSD1 knockdown sensitized RSK-subtype cells but induced chemoresistance in KRAS-subtype cells.
- Mitochondrial dysfunction and impaired mitophagy characterize KRAS-subtype PDAC.
- Targeting mitochondrial respiration or mitophagy reversed LSD1-mediated chemoresistance.
- LSD1 regulates GLS2, controlling glutamine metabolism and subtype-specific metabolic reprogramming.
Conclusions:
- The LSD1-GLS2 axis acts as a metabolic switch influencing PDAC chemosensitivity.
- Mitochondrial fitness is a key determinant of chemoresistance in a subtype-specific manner.
- Strategies targeting mitochondrial pathways offer a framework for developing subtype-specific PDAC therapies.