The creatine-phosphagen system is mechanoresponsive in pancreatic adenocarcinoma and fuels invasion and metastasis

Papalazarou, V., Zhang, T., Paul, N. R., Juin, A., Cantini, M. , Maddocks, O. D.K. , Salmeron-Sanchez, M. and Machesky, L. (2020) The creatine-phosphagen system is mechanoresponsive in pancreatic adenocarcinoma and fuels invasion and metastasis. Nature Metabolism, 2(1), pp. 62-80. (doi: 10.1038/s42255-019-0159-z) (PMID:32694686)

205763.pdf - Accepted Version



Pancreatic ductal adenocarcinoma is particularly metastatic, with dismal survival rates and few treatment options. Stiff fibrotic stroma is a hallmark of pancreatic tumours, but how stromal mechanosensing affects metastasis is still unclear. Here, we show that mechanical changes in the pancreatic cancer cell environment affect not only adhesion and migration, but also ATP/ADP and ATP/AMP ratios. Unbiased metabolomic analysis reveals that the creatine–phosphagen ATP-recycling system is a major mechanosensitive target. This system depends on arginine flux through the urea cycle, which is reflected by the increased incorporation of carbon and nitrogen from L-arginine into creatine and phosphocreatine on stiff matrix. We identify that CKB is a mechanosensitive transcriptional target of YAP, and thus it increases phosphocreatine production. We further demonstrate that the creatine–phosphagen system has a role in invasive migration, chemotaxis and liver metastasis of cancer cells.

Item Type:Articles
Additional Information:We acknowledge CRUK Beatson Institute Core Services and Advanced Technologies (C596/A17196), and especially Beatson Advanced Imaging Resource (BAIR). V.P. is supported by a CRUK Glasgow Centre studentship (A18076) to M.S.S. and L.M.M. L.M.M. is supported by a CRUK core grant A15673.
Glasgow Author(s) Enlighten ID:Juin, Dr Amelie and Salmeron-Sanchez, Professor Manuel and Maddocks, Professor Oliver and Machesky, Professor Laura and Papalazarou, Mr Vasileios and Zhang, Mr Tong and Cantini, Dr Marco
Authors: Papalazarou, V., Zhang, T., Paul, N. R., Juin, A., Cantini, M., Maddocks, O. D.K., Salmeron-Sanchez, M., and Machesky, L.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Nature Metabolism
Publisher:Nature Research
ISSN (Online):2522-5812
Published Online:20 January 2020
Copyright Holders:Copyright © 2020 Springer Nature
First Published:First published in Nature Metabolism 2(1): 62-80
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301636Metabolic drivers of pancreatic cancer cell migration and metastasisLaura MacheskyMedical Research Council (MRC)MR/R017255/1CS - Beatson Institute for Cancer Research
173192Engineering growth factor microenvironments- a new therapeutic paradigm for regenerative medicineManuel Salmeron-SanchezEngineering and Physical Sciences Research Council (EPSRC)EP/P001114/1ENG - Biomedical Engineering
303613Engineered microenvironments to harvest stem cell response to viscosity for cartilage repairMarco CantiniMedical Research Council (MRC)MR/S005412/1ENG - Biomedical Engineering
171982Targeting Tumour Metabolism for Cancer Therapy and Diagnosis.Oliver MaddocksCancer Research UK (CRUK)C53309/A19702Institute of Cancer Sciences