Abstract BACKGROUND Glioblastoma (GB) is the most common primary tumour in the adult brain. Despite surgical excision of the tumour followed by radiotherapy and chemotherapy, patients’ prognoses remain unfavourable, with a high relapse rate and an overall survival of 15 months. Tumour recurrence takes its source in the infiltrative nature of some GB cells that escaped resection, among which were revealed GB stem-like cells (GSCs). Building upon the lactate shuttle model proposed by Pellerin et al. (Dev Neurosci., 1998) involving astrocytes and neurons, recent findings unveiled a metabolic symbiosis between the GB tumour core and its invasive population, based on lactate exchanges (Guyon J. et al., EMBO Mol. Med., 2022). Resection, while pivotal, disrupts this spatial and metabolic equilibrium established between cells within the tumour core and the invasive population. MATERIAL AND METHODS We hypothesized that tumour resection, through the disturbance of the intratumoral metabolic organization, induces a metabolic reprogramming of the remaining GB invasive cells. An in vitro model of resection was engineered through the chronic treatment/removal of lactate. The link between post-resection metabolic adaptation and tumour regrowth was further explored in vivo through novel resection models in mice harbouring intracranial GB. RESULTS In vitro results showed that the mitochondria of lactate-starved cells downregulate their activity. This alteration in mitochondrial function correlates with increased reactive oxygen species (ROS) production, acting as a signalling entity that may influence the expression of downstream metabolic players. We observed modulations of proteins linked to the lactate metabolism, such as the LDHs, CD147/Basigin, and MCT1. MCT1 is a lactate transporter that tends to be upregulated under tumour resection or lactate deprivation. This increase appears alongside its chaperone, CD147, suggesting that MCT1 is correctly positioned and active in the membrane. We also observed behavioural modulations in GB cells deprived of lactate, tending towards a reprise of proliferation and a reduction of the invasion, thus correlating with tumour recurrence in patients after surgery. Spatial transcriptomics correlated with Mass Spec Imaging was performed to determine global metabolic adaptations in post-resection GB. Initial outcomes from challenging resected tumours in vivo with LDH inhibitors showed a decrease in tumour relapse. CONCLUSION Initial evidence suggests that in vivo resection of GB and in vitro lactate starvation on GB cells induce a shift from an oxidative/invasive metabolism to a more glycolytic and proliferative state. Overall, developing therapies that impair GSCs adaptation appears promising to prevent tumour recurrence in patients.
Davoust et al. (Wed,) studied this question.