Research Highlights

spherical morphology. PDAC cells grown on soft substrates had higher levels of aerobic than those grown on stiff substrates, whereas PDAC cells grown on stiffer substrates had higher mitochondrial respiratory activity, and mitochon- dria were more elongated and fused, overall indicating that mitochondrial homeostasis and ATP production Credit: Lara Crow/Springer Nature Limited Nature Crow/Springer Lara Credit: was favoured on stiff substrates. Metabolomics analyses indicated an increased ATP turnover rate on stiffer substrates, accompanied by changes in metabolites involved in ATP recycling, with an increased How to run through mud phosphocreatine (pCr):creatine ratio (indicating higher rates of Cancer cells encounter changes in rate, inhibition of myosin II activity ATP recycling via the pCr-creatine extracellular environments depend- decreased PFKP expression and (CK) system) on stiffer ing on their localization in the body the link glycolytic rate in HBECs, as did substrates. The flux of arginine or tissue. These can be regular exter- between inhibition of F-actin polymerization. (a urea cycle metabolite) was nal forces such as those occurring By contrast, PFKP expression and switched on stiffer ECM towards in the lungs during respiration, or the actin glycolytic rates in KRAS-mutated synthesis of creatine, whereas changes during cancer development cytoskeleton non-small cell lung cancer (NSCLC) softer substrates promoted urea and progression. Cancer cell metab­ and the cells were resistant to this treatment. cycle activity. In line with increased olism can underlie tumour growth and glycolytic rate This suggested that the link between engagement of the pCr-CK system progression, yet how cell metabolism the actin cytoskeleton and the glyco- to reduce ATP diffusion during responds to mechanical forces, for in untrans­ lytic rate in untransformed cells was high-demand processes such as example during invasion, is unclear. formed cells overridden in transformed cells. cancer invasion, expression of Two studies have shed light on was over­ridden Exploring a post-transcriptional CK B-type (CKB), which catalyses these processes. mechanism of PFKP regulation, the transfer of phosphate between To explore the interdependence in transformed acute inhibition of the proteasome ATP and creatine to form pCr, was between cell metabolism and mecha­ cells rescued endogenous PFKP in mechanosensitive. Ckb was identified nics, Park et al., who report their HBECs grown on soft substrates. as a transcriptional target of YAP, findings in Nature, used human bron- The E3 ubiquitin ligase TRIM21 was which is activated by mechanical chial epithelial cells (HBECs), which responsible for PFKP degradation stress, leading to increased expres- change in morphology when grown in untransformed cells on soft sion of CKB on stiffer substrates on stiff or soft collagen substrates. substrates. TRIM21 overexpression and thereby driving ATP recycling. Metabolomics analyses showed that in NSCLC cells decreased PFKP Further analysis showed that CKB metabolites of glycolysis and the expression on soft substrates, and and activity of the pCr-CK system tricarboxylic acid (TCA) cycle, as well TRIM21 and F-actin co-localized was required for directed migration as the glycolytic rate, were downregu­ and interacted – further analyses and ECM invasion of PDAC cells. lated in HBECs grown on soft sub- suggested that NSCLC cells have In vivo, the metastatic burden in strates compared with those grown stronger F-actin bundles than HBECs the liver of intrasplenically injected on stiff substrates. Also, all three and are able to sequester and inhibit CKB-depleted KPC cells was isoforms of TRIM21 on soft substrates. decreased compared with KPC cells. (PFK), which catalyses a rate-limiting Papalarazou et al., who report Whereas lung cancer cells step of glycolysis, were downregu- their findings in Nature Metabolism, stabilized their glycolytic rate lated, and lower PFK activity was analysed pancreatic ductal adeno- in response to mechanical cues, observed. The authors focused on carcinoma (PDAC), which is highly pancreatic cancer cells engaged in the platelet PFK (PFKP) isoform, the fibrotic and shows extensive extra- extensive metabolic reprogramming, most ubiquitously expressed isoform cellular matrix (ECM) remodelling. showcasing mechanisms by which across human tissues. In contrast to Pancreatic cancer cells derived from cancer cells adapt to mechanical untransformed HBECs, oncogeni- Pdx1-cre;LSL-KrasG12D;LSL-Trp53R172H forces in their local environments. cally transformed HBECs (lacking mice (KPC cells) were grown on Ulrike Harjes G12V TP53 and overexpressing KRAS fibronectin-coated hydrogel of Original articles Park, J. S. et al. Mechanical and MYC) maintained their glycolytic increasing degrees of stiffness regulation of glycolysis via cytoskeleton architecture. Nature 578, 621–626 (2020) | rate as well as their PFKP expression (0.7 –38 kPa) and glass (2–4 GPa); Papalarazou, V. et al. The creatine–phosphagen on soft substrates. decreasing stiffness led cells to system is mechanoresponsive in pancreatic Exploring a link between acto- change from a more spread and adenocarcinoma and fuels invasion and metastasis. Nat. Metab. 2, 62–80 (2020) myosin contractility and glycolytic elongated morphology to a more

NAtuRe RevIews | Cancer volume 20 | APRIL 2020 | 201