Glucose deprivation induces AMPK-dependent α-actinin-4 expression to sustain energy efficient non-proteolytic migration

Crosstalk between tumor microenvironmental factors, such as extracellular matrix (ECM) stiffness and metabolic pathways, regulate cell invasive phenotype in cancer cells. ECM stiffening leads to the collapse of blood vessels leading to oxygen deprivation and nutrient stress. The individual and combined effect of these two factors on the mode of invasion of cancer cells remains poorly understood. Here, we show that in breast cancer cells, glucose deprivation induces a switch from an energy-demanding proteolytic mode of migration to an energy efficient non-proteolytic mode of migration. Energy demands met by OXPHOS and nuclear softening sustain this mode of migration. We further show that the energy sensor AMPK mediates this switch through transcriptional activation of the mechanoresponsive actin crosslinking protein α-actinin-4. Collectively, our results demonstrate how AMPK fine-tunes mode of invasion under nutrient constraints by transcriptional activation of α-actinin-4.