ECM mechanics and spatiotemporal energetics in pancreatic cancer

Unbalanced cues from the extracellular matrix (ECM) govern pancreatic tumorigenesis and dissemination. Stiff fibrotic stroma and cancer cell mechanosensing regulate cell proliferation, migration and invasion. Such key processes are highly dependent on energy availability and need to be fuelled by metabolic adaptations to tumorigenic microenvironments. However, it is still unknown how ECM mechanics influence cellular energetics and metabolism as well as how cells meet their ATP requirements during invasion and metastasis. We found that pancreatic cancer cells tune their metabolic networks to favour ATP production on stiff ECM. This process appeared dependent on mitochondrial fusion and polarization on stiff substrata as well as in pseudopods formed during ECM invasion. In addition, this was accompanied by a mechano-dependent regulation of ATP recycling through the creatine phosphagen system. The cytoplasmic creatine kinase CKB was expressed on stiff substrata in a YAP dependent manner providing a critical advantage to the invasion capacity of pancreatic cancer cells. Collectively our results indicate that ECM mechanics can positively regulate tumour invasion by favouring ATP production and sharpening the gradient of ATP vs ADP through CKB activity. Our study highlights the importance of this ATP recycling circuit as a mechanism generating an efficient energy balance within the cytoplasm boosting invasion. Interestingly, targeting creatine phosphorylation hindered migration and invasion in 2D and 3D, revealing CKB as a potentially druggable target against the spread of pancreatic cancer