Fig. 10: AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin II dependent cell migration.

Highly invasive but weakly adhesive rounded-amoeboid cancer cells harbour high levels of cortical Myosin II activity and exert low magnitude traction forces into extracellular matrix (ECM). Low adhesion to the matrix results in decreased engagement in mitochondrial metabolism and alterations in ATP and AMP intracellular levels that lead to AMP-activated protein kinase (AMPK) activation. Once AMPK is active, it directly phosphorylates the crucial regulator of cytoskeletal dynamics Myosin phosphatase (Myosin phosphatase target subunit 1, MYPT1) in the key residue for its inactivation, leading to increased Myosin Light Chain phosphorylation and increased overall Myosin II activity. At the same time, AMPK induces mitochondrial fission through the phosphorylation of Mitochondrial Fission Factor (MFF), which sustains the imbalance in energy levels, further boosting AMPK signalling and Myosin II activation. In contrast, highly adhesive elongated-mesenchymal cells present highly fused and active mitochondria. This provides energy for mesenchymal cancer cells to exert strong adhesive traction stress, while it maintains lower levels of AMPK signalling, resulting in moderate Myosin II activity. Strong adhesions in elongated-mesenchymal cells rely on Discoidin Domain Receptor 1 (DDR1) collagen receptor. Reducing DDR1-dependent adhesion, inhibiting mitochondrial fusion or inducing AMPK activity in elongated-mesenchymal cells promotes the transition to rounded-amoeboid efficient migration/invasion and all its cytoskeletal/mitochondrial features. (Created with BioRender.com).