PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia

Saliakoura et al. find that PLC gamma 1 is suppressed in hypoxic KRAS-mutant lung cancer cells, which impairs Ca(2+)entry into the mitochondria and promotes glycolysis to enhance tumour progression. Mutant KRAS modulates the metabolic plasticity of cancer cells to confer a growth advantage during hypoxia, but the molecular underpinnings are largely unknown. Using a lipidomic screen, we found that PLC gamma 1 is suppressed during hypoxia in KRAS-mutant human lung adenocarcinoma cancer cell lines. Suppression of PLC gamma 1 in hypoxia promotes a less oxidative cancer cell metabolism state, reduces the formation of mitochondrial reactive oxygen species and switches tumour bioenergetics towards glycolysis by impairing Ca(2+)entry into the mitochondria. This event prevents lipid peroxidation, antagonizes apoptosis and increases cancer cell proliferation. Accordingly, loss of function ofPlcg1in a mouse model ofKras(G12D)-driven lung adenocarcinoma increased the expression of glycolytic genes, boosted tumour growth and reduced survival. In patients with KRAS-mutant lung adenocarcinomas, low PLC gamma 1 expression correlates with increased expression of hypoxia markers and predicts poor patient survival. Thus, our work reveals a mechanism of cancer cell adaptation to hypoxia with potential therapeutic value.