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

Vassilis Papalazarou, Tong Zhang, Nikki R. Paul, Amelie Juin, Marco Cantini, Oliver D.K. Maddocks, Manuel Salmeron-Sanchez, Laura M. Machesky

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)62-80
Number of pages19
JournalNature Metabolism
Volume2
Issue number1
DOIs
Publication statusPublished - Jan 1 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Internal Medicine
  • Cell Biology

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  • Cite this

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