TY - JOUR
T1 - The creatine–phosphagen system is mechanoresponsive in pancreatic adenocarcinoma and fuels invasion and metastasis
AU - Papalazarou, Vassilis
AU - Zhang, Tong
AU - Paul, Nikki R.
AU - Juin, Amelie
AU - Cantini, Marco
AU - Maddocks, Oliver D.K.
AU - Salmeron-Sanchez, Manuel
AU - Machesky, Laura M.
N1 - Funding Information:
We acknowledge CRUK Beatson Institute Core Services and Advanced Technologies (C596/A17196), and especially Beatson Advanced Imaging Resource (BAIR). We thank S. Karim for KPC cell lines. We also thank C. Nixon and the Beatson Histology Facility, D. Bryant and his lab for advice, J. Murray for generating fibroblast-derived matrices and E. J. McGhee for assistance with SHG microscopy. We thank M. Neilson for assistance in analysis and statistical advice. We also thank T. Hamilton, C. Baxter and E. Onwubiko for helping with intrasplenic surgery. We thank T. Pompe (University of Leipzig) for providing analysis software for TFM experiments. We thank H. Spence and R.H. Insall for advice and discussion. 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; N.R.P. is supported by an MRC grant to L.M.M. (MR/R017255/1). M.S.S. is funded by an EPSRC Programme Grant (EP/P001114/1). M.C. is funded by an MRC UKRI/Rutherford Fund fellowship (MR/S005412/1). O.M. and T.Z. are funded by a Cancer Research UK Career Development Fellowship (C53309/A19702).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s42255-019-0159-z
DO - 10.1038/s42255-019-0159-z
M3 - Article
AN - SCOPUS:85078271753
SN - 2522-5812
VL - 2
SP - 62
EP - 80
JO - Nature Metabolism
JF - Nature Metabolism
IS - 1
ER -
