Galectin-1 modulates glycolysis through a GM1-galactose–dependent pathway to promote hyperthermia resistance in HCC

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BACKGROUND AND AIMS: Thermal ablation is the standard-of-care treatment modality with curative intent for early-stage nonresectable HCC, but a durable response is limited, with up to 40% of patients with HCC eventually experiencing local recurrence on posttreatment surveillance. While thermal ablation has been established to cause immediate cell death in the center of the thermal ablation zone, its metabolic impact in the peri-ablational region remains unclear. We aimed to elucidate the metabolic mechanism by which Galectin-1 (Gal-1) promotes thermal-ablation-induced hyperthermia resistance in HCC and demonstrate the therapeutic potential of inhibiting Gal-1 in combination with thermal ablation in vivo . APPROACH AND RESULTS: Proteomic analysis was performed using an untargeted approach on pre-ablation formalin-fixed paraffin-embedded biopsy specimens of thermal ablation responders (n=32) and nonresponders (n=23). Gal-1 was found to be overexpressed in thermal ablation nonresponders compared with responders. Moreover, HCC with Gal-1 overexpression demonstrated reduced sensitivity to hyperthermia in vitro and increased utilization of glycolysis and the downstream tricarboxylic acid (TCA) cycle under hyperthermia-induced stress. Gal-1-overexpressing HCC enhanced its metabolic utilization through Gal-1-facilitated GM1-ganglioside breakdown, producing galactose to increase the metabolic influxes into glycolysis and consequently the downstream TCA cycle. In-vivo studies showed that inhibiting Gal-1 in combination with thermal ablation significantly reduced tumor size compared with either monotherapy thermal ablation or Gal-1 inhibition alone. CONCLUSIONS: Gal-1 can mediate hyperthermia resistance in HCC and can potentially be modulated as a therapeutic target to reduce rapid progression after thermal ablation.

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