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

研究成果: ジャーナルへの寄稿学術誌査読

47 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)62-80
ページ数19
ジャーナルNature Metabolism
2
1
DOI
出版ステータス出版済み - 1月 1 2020
外部発表はい

!!!All Science Journal Classification (ASJC) codes

  • 内科学
  • 内分泌学、糖尿病および代謝内科学
  • 細胞生物学
  • 生理学(医学)

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