Salk Institute scientists recently published work demonstrating how lung cancer cells are able to break loose from lung tissue and invasively metastasize to other vital organs, a characteristic occurrence that is responsible for death within 5 years of diagnosis in 83% of patients with lung cancer. The newly discovered pathway may also help researchers understand and treat the spread of melanoma and cervical cancers. The study fully defines an adenosine monophosphate-activated protein kinase (AMPK)–independent phosphorylation cascade essential for liver kinase B1 (LKB1)–dependent control of metastatic behavior.
LKB1 is a tumor suppressor gene whose loss is associated with increased metastatic potential. DIXDC1 is a scaffolding protein frequently down-regulated in human cancers; the loss of DIXDC1, similar to that of LKB1, is known to lead to increased cell invasion. DIXDC1 is a substrate of related kinases MARK1 and MARK4, which are required for LKB1 to communicate with DIXDC1. When LKB1 functions normally, it “turns on” DIXDC1, keeping cells where they are. Cancer, however, can interfere with this signal. “Turned on,” DIXDC1 causes sprouting of about a half-dozen large, sticky focal adhesion complexes that protrude from the cell membrane and function as anchors. “Turned off,” the adhesion complexes decrease in size and become more numerous, and act like little hands pulling the cells in response to extracellular signals and contributing to the ability of the cells to break loose and invade the body.
Currently no treatments are available for cancers harboring LKB1 or DIXDC1 mutations, but therapies targeting focal adhesion enzymes are in early-stage clinical trials. For further understanding of this discovery, hear the scientists’ own explanation on YouTube: http://www.youtube.com/watch?v=ta0Ly_-4MsQ
Contributed by William Yarnall, RPh, CCP