Editors' ChoiceCancer

Mechanosensing metabolically moves cancer cells

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Science Signaling  18 Feb 2020:
Vol. 13, Issue 619, eabb2935
DOI: 10.1126/scisignal.abb2935

A stiff stroma triggers metabolic changes that support invasion and metastasis in pancreatic cancer cells.

An increase in the stiffness of the extracellular matrix activates a mechanotransduction pathway that often results in the nuclear accumulation of the transcriptional coregulator YAP and altered gene expression patterns in many cell types. Cancer cells remodel the extracellular matrix in the stroma, and stiffer matrices promote tumor progression and metastasis. Papalazarou et al. investigated the metabolic link between mechanotransduction and metastasis of pancreatic tumor cells (see also Liberti and Birsoy). Compared with those on a softer matrix, pancreatic cancer cells on stiffer matrices showed increased actin organization, increased nuclear accumulation of YAP, shunting of arginine toward creatine biosynthesis, and an increased ratio of phosphocreatine to creatine. Phosphocreatine is a component of the creatine-phosphagen system that serves as a reservoir for high-energy phosphates used to rapidly recycle ATP and that is generated by the action of creatine kinases (CKs) on creatine. Oxidative phosphorylation as well as mitochondrial fusion and elongation were increased in pancreatic cancer cells on stiffer matrices. The expression of Ckb was induced in pancreatic cancer cells on stiffer matrices in a YAP-dependent manner. In vitro migration on stiff matrices and Matrigel invasion by pancreatic cancer cells was decreased by knockdown of CKB or by application of cyclocreatine, a phosphocreatine analog that is a poor phosphate donor. Similarly, chemotactic migration and the increase in actin treadmilling that occurred in the pseudopods of invading cells were attenuated by cyclocreatine application or CKB knockdown. In addition, cyclocreatine prevented spheroids of pancreatic cancer cells from increasing collagen deposition around themselves. In mice transplanted with pancreatic cancer cells in the spleen, cyclocreatine supplementation or CKB knockdown in these cells decreased metastasis to the liver. Thus, mechanical cues initiated by stiff stroma trigger metabolic changes that support invasive and metastatic behavior in pancreatic cancer cells.

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