At the cellular level, migrating cancer cells have proton-exporting machinery, such as sodium–hydrogen exchangers (NHE1) or sodium-bicarbonate cotransporters (NBCn1), coupled to CAIX at the front of their invadopodia, resulting in a more acidic pHe at the leading edge of the migrating cell [83,119] which activates proteases, e.g., lysosomal cathepsins, that then degrade the host’s extracellular matrix [139,140]. The gene discussed is CA9; the disease is cancer.