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)
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205763.pdf - Accepted Version 181MB |
Abstract
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. |
| Status: | Published |
| Refereed: | Yes |
| 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: | 2522-5812 |
| 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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