Creatine promotes metastatic dissemination

The molecular regulation of cancer metastasis is not fully understood. In this issue Cell Metabolism, Zhang et al., 2021Zhang L. Zhu Z. Yan H. Wang W. Wu F. Q. Shi G. Du J. Cai al.Creatine promotes through activation Smad2/3.Cell Metab. 2021; 33 (this issue): 1111-1123Abstract Full Text PDF Scopus (22) Google Scholar discover that creatine in mice by promoting the MPS1-Smad2/3 axis. Metastasis involves spread cells from primary tumor to surrounding tissues and represents main cause cancer-related mortality (Chaffer Weinberg, 2011Chaffer C.L. Weinberg R.A. A perspective on cell metastasis.Science. 2011; 331: 1559-1564Crossref PubMed (3156) Scholar; Lehuédé 2016Lehuédé C. Dupuy Rabinovitch R. Jones R.G. Siegel P.M. Metabolic plasticity as a determinant growth metastasis.Cancer Res. 2016; 76: 5201-5208Crossref (160) Scholar). Cancer must adapt their metabolism meet energetic biosynthetic demands accompany rapid proliferation colonization distinct metastatic sites whose microenvironment can differ widely site. Through reversible transfer phosphoryl group ATP creatine, kinases maintain high ATP/ADP ratios at utilization (Wallimann 1992Wallimann T. Wyss M. Brdiczka D. Nicolay K. Eppenberger H.M. Intracellular compartmentation, structure function kinase isoenzymes with fluctuating energy demands: ‘phosphocreatine circuit’ for cellular homeostasis.Biochem. 1992; 281: 21-40Crossref (1573) Thus, buffering key creatine. Creatine be transported circulation into target highly specific transporter (SLC6A8), or it synthesized intracellularly coordinated action glycine amidinotransferase (GATM) guanidinoacetate N-methyltransferase (GAMT) (Kazak Cohen, 2020Kazak Cohen P. metabolism: homeostasis, immunity biology.Nat. Rev. Endocrinol. 2020; 16: 421-436Crossref (50) has been linked metastastatic dissemination, whereby thought fuel requirments migrating (Papalazarou 2020Papalazarou V. Paul N.R. Juin A. Cantini Maddocks O.D.K. Salmeron-Sanchez Machesky L.M. creatine-phosphagen system mechanoresponsive pancreatic adenocarcinoma fuels invasion metastasis.Nat 2: 62-80Crossref (42) al. found supplementation promoted progression shortened survival orthotopic colorectal (CRC) breast models (Zhang Silencing Slc6a8 limited accumulation inhibited pro-metastatic effects supplementation. These data established role dietary (Figure 1). Next, co-workers discovered synthesis enzymes, Gatm Gamt, were elevated human samples compared tumors CRC other cancers, suggesting ability exploit may conserved. Moreover, expression was associated poorer prognosis patients. Consistent these correlations, overexpression promoted, while silencing suppressed, liver metastases mice. Remarkably, prolonged similar extent frontline chemotherapy, 5-fluorouracil, combined use more than either treatment alone. Mechanistically, (phosphorylation) Smad2 Smad3 induction genes, Snail Slug have previously implicated (Cai 2019Cai Xia Li Ni S. Song X. Tumor-associated macrophages derived TGF-β‒induced epithelial mesenchymal transition Smad2,3-4/Snail signaling pathway.Cancer Treat. 2019; 51: 252-266Crossref (47) Pharmacological genetic blockade monopolar spindle 1 (MPS1) activity abrogated creatine-mediated phosphorylation Smad2/3, suppressed metastasis, survival, implicating creatine-dependent MPS1 an upstream regulator Smad2/3 activation. Notably, re-established upon rescued wild-type, but T685-mutated MPS1, Mps1-depleted cells. T685 mouse (T686 human) critical signaling. findings colleagues complement growing list recent studies As authors mention, outsanding question lies understanding mechanism regulating Other worthy pursuits would differential tumors. observed metastasis; however, appeared Recent work shown adipocyte-derived growth, specifically obesity (Maguire 2021Maguire O.A. Ackerman S.E. Szwed S.K. Maganti A.V. Marchildon Huang Kramer D.J. Rosas-Villegas Gelfer Turner L.E. al.Creatine-mediated crosstalk between adipocytes regulates obesity-driven cancer.Cell 33: 499-512.e6Abstract appears depending nutritional status host. come diet, cell-autonomously Scholar), neighboring peri-tumoral (Loo 2015Loo J.M. Scherl Nguyen Man F.Y. E. Zeng Saltz Paty P.B. Tavazoie S.F. Extracellular metabolic energetics promote progression.Cell. 2015; 160: 393-406Abstract (222) Maguire variation sources explain, least partly, some biological different settings. Could product factor responses lean obese hosts? phosphorylated phosphocreatine kinases. Work indicated via SLC6A8 trigger properties synthesis? Transport directly bypass requirement invest make phosphocreatine. Now first gene, Ckb, conditionally manipulated cell-type-specific manner (Rahbani 2021Rahbani J.F. Roesler Hussain M.F. Samborska B. Dykstra C.B. Tsai Jedrychowski M.P. Vergnes Reue Spiegelman B.M. Kazak B controls futile cycling thermogenic fat.Nature. 590: 480-485Crossref (26) will possible study how host influences progression. Indeed, CKB recently dissemination model This area surely benefit conditional manipulation all genes. engage programs site (Dupuy 2015Dupuy Tabariès Andrzejewski Dong Blagih Annis M.G. Omeroglu Gao Leung Amir al.PDK1-dependent reprogramming dictates potential 22: 577-589Abstract (308) It interesting determine if properties. primarily lungs. Is just consequence systems used, are metabolically wired support manner? seem intuitive responsible lion’s share endogenous promotion lung less clear, deserves further investigation. Finally, there metastic independent cell’s capacity harness kinase-PCr circuit? sum, demonstrate connection using series elegant well-executed vivo approaches. They identify cascade acts MPS1-SMAD2/3-SNAIL/SLUG Activation pathway renders metastatic. Importantly, blocking pharmacologically genetically therapeutically chemotherapy even better when used combination. described done mice, remains determined mechanisms occur Further also provide fundamental insight physiology. supported Canadian Institutes Health Research grant ( PJT-159529 ) Foundation Innovation John Evans Leaders Fund 37919 (to L.K.). L.K. Canada Chair Adipocyte Biology. declare no competing interests. Smad2/3Zhang al.Cell MetabolismApril 2, 2021In BriefCreatine improve muscle mass healthy people. However, report levels endogenously activating MPS1. Targeting prevents metastasis. Full-Text Open Archive