Metabolic rewiring of cancer cells induces metastasis via ERK5 but triggers recognition by NK cells

Metastasis is largely controlled by Natural Killer (NK) cell-mediated immune surveillance. To colonize new environments, cancer cells undergo epithelial to mesenchymal transition (EMT), which allows them to detach and migrate. EMT is fueled by fatty acid oxidation (FAO), which partially replaces glycolytic-based tumor metabolism. Whether metabolic rewiring affects the targeting of cancer cells by NK cells remains unknown. Here, we show that forcing solid cancer cells to perform FAO by inhibiting pyruvate dehydrogenase kinase 1 with dichloroacetate (DCA) activates extracellular signal-regulated kinase-5 (ERK5), triggering EMT and tumor cell migration and invasion. Concomitantly, FAO induces the expression of ligands that mediate NK cell recognition. Consequently, NK cells better infiltrated DCA-treated 3D tumor spheroids, where they exerted their cytotoxic effects. DCA-treated cells showed increased migration in a zebrafish model, whereas metastasis from mammary cancer cells grafted into immune-deficient mice was enhanced by DCA. These migrating/metastatic cells are preferentially killed by NK cells, which strongly limit their invasive potential. Hence, FAO promotes both metastasis and NK-mediated tumor surveillance, highlighting the Achilles’ heel of metastatic cells, which may offer new therapeutic opportunities.