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Melanoma pp 99-122 | Cite as

Melanoma Metabolism

  • Franziska Baenke
  • Nathalie Dhomen
  • Eyal Gottlieb
  • Richard MaraisEmail author
Reference work entry

Abstract

The rewiring of metabolic pathways is one of the hallmarks of cancer and essential for tumorigenesis. It stems from the need of cancer cells to adapt their biosynthetic and bioenergetic demands in order to allow unrestricted proliferation and growth. Melanoma and other cancer cells exhibit a remarkable flexibility within a complex network of metabolic pathways, allowing them to use their often limited resources and direct them to the processes best placed to maximize their growth and survival. For example, during melanomagenesis, cells will often switch their energy production from mitochondrial metabolism to glycolysis, because the products of glycolysis can easily be shifted to essential pathways for macromolecule biosynthesis. Many of these metabolic alterations are initiated in response to signaling cues from genetic alterations that initiated melanomagenesis in the first place, which suggests that the events required to transform cells to malignancy must allow cells to meet their biosynthetic and bioenergetic needs. During progression, melanomas appear to display metabolic heterogeneity as vital nutrient sources become scarce and the tumor seeks to overcome these restrictions. As further insights into the metabolic rewiring that occurs during melanoma development and progression are gained, opportunities to target these vulnerabilities for therapeutic benefit may be exploited.

This book chapter provides a brief overview of important metabolic pathways and how these become reprogrammed by known oncogenes that are frequently altered in human melanomas. How these metabolic vulnerabilities are being targeted for clinical use will also be highlighted.

Keywords

Melanocytes Melanoma Metabolism Signaling Nutrients Hypoxia Autophagy Microenvironment 

References

  1. Allen E, Mieville P, Warren CM, Saghafinia S, Li L, Peng MW, Hanahan D (2016) Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling. Cell Rep 15(6):1144–1160.  https://doi.org/10.1016/j.celrep.2016.04.029CrossRefPubMedPubMedCentralGoogle Scholar
  2. Baenke F, Peck B, Miess H, Schulze A (2013) Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Dis Model Mech 6(6):1353–1363.  https://doi.org/10.1242/dmm.011338CrossRefPubMedPubMedCentralGoogle Scholar
  3. Baenke F, Chaneton B, Smith M, Van Den Broek N, Hogan K, Tang H, Viros A, Martin M, Galbraith L, Girotti MR, Dhomen N, Gottlieb E, Marais R (2016) Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells. Mol Oncol 10(1):73–84.  https://doi.org/10.1016/j.molonc.2015.08.003CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bedogni B, Powell MB (2009) Hypoxia, melanocytes and melanoma – survival and tumor development in the permissive microenvironment of the skin. Pigment Cell Melanoma Res 22(2):166–174.  https://doi.org/10.1111/j.1755-148X.2009.00553.xCrossRefPubMedPubMedCentralGoogle Scholar
  5. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126(1):107–120.  https://doi.org/10.1016/j.cell.2006.05.036CrossRefPubMedGoogle Scholar
  6. Bettum IJ, Gorad SS, Barkovskaya A, Pettersen S, Moestue SA, Vasiliauskaite K, Tenstad E, Oyjord T, Risa O, Nygaard V, Maelandsmo GM, Prasmickaite L (2015) Metabolic reprogramming supports the invasive phenotype in malignant melanoma. Cancer Lett 366(1):71–83.  https://doi.org/10.1016/j.canlet.2015.06.006CrossRefPubMedGoogle Scholar
  7. Bohme I, Bosserhoff AK (2016) Acidic tumor microenvironment in human melanoma. Pigment Cell Melanoma Res.  https://doi.org/10.1111/pcmr.12495CrossRefGoogle Scholar
  8. Boroughs LK, DeBerardinis RJ (2015) Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol 17(4):351–359.  https://doi.org/10.1038/ncb3124CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJ, Tonc E, Schreiber RD, Pearce EJ, Pearce EL (2015a) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162(6):1229–1241.  https://doi.org/10.1016/j.cell.2015.08.016CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chang YL, Gao HW, Chiang CP, Wang WM, Huang SM, Ku CF, Liu GY, Hung HC (2015b) Human mitochondrial NAD(P)(+)-dependent malic enzyme participates in cutaneous melanoma progression and invasion. J Invest Dermatol 135(3):807–815.  https://doi.org/10.1038/jid.2014.385CrossRefPubMedGoogle Scholar
  11. Damsky W, Micevic G, Meeth K, Muthusamy V, Curley DP, Santhanakrishnan M, Erdelyi I, Platt JT, Huang L, Theodosakis N, Zaidi MR, Tighe S, Davies MA, Dankort D, McMahon M, Merlino G, Bardeesy N, Bosenberg M (2015) mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation. Cancer Cell 27(1):41–56.  https://doi.org/10.1016/j.ccell.2014.11.014CrossRefPubMedPubMedCentralGoogle Scholar
  12. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, Scrimieri F, Winter JM, Hruban RH, Iacobuzio-Donahue C, Kern SE, Blair IA, Tuveson DA (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475(7354):106–109.  https://doi.org/10.1038/nature10189CrossRefPubMedPubMedCentralGoogle Scholar
  13. DeNicola GM, Chen PH, Mullarky E, Sudderth JA, Hu Z, Wu D, Tang H, Xie Y, Asara JM, Huffman KE, Wistuba II, Minna JD, DeBerardinis RJ, Cantley LC (2015) NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet 47(12):1475–1481.  https://doi.org/10.1038/ng.3421CrossRefPubMedPubMedCentralGoogle Scholar
  14. Denoyelle C, Abou-Rjaily G, Bezrookove V, Verhaegen M, Johnson TM, Fullen DR, Pointer JN, Gruber SB, Su LD, Nikiforov MA, Kaufman RJ, Bastian BC, Soengas MS (2006) Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway. Nat Cell Biol 8(10):1053–1063.  https://doi.org/10.1038/ncb1471CrossRefPubMedGoogle Scholar
  15. Efeyan A, Comb WC, Sabatini DM (2015) Nutrient-sensing mechanisms and pathways. Nature 517(7534):302–310.  https://doi.org/10.1038/nature14190CrossRefPubMedPubMedCentralGoogle Scholar
  16. Falck Miniotis M, Arunan V, Eykyn TR, Marais R, Workman P, Leach MO, Beloueche-Babari M (2013) MEK1/2 inhibition decreases lactate in BRAF-driven human cancer cells. Cancer Res 73(13):4039–4049.  https://doi.org/10.1158/0008-5472.CAN-12-1969CrossRefPubMedGoogle Scholar
  17. Filipp FV, Ratnikov B, De Ingeniis J, Smith JW, Osterman AL, Scott DA (2012a) Glutamine-fueled mitochondrial metabolism is decoupled from glycolysis in melanoma. Pigment Cell Melanoma Res 25(6):732–739.  https://doi.org/10.1111/pcmr.12000CrossRefPubMedPubMedCentralGoogle Scholar
  18. Filipp FV, Scott DA, Ronai ZA, Osterman AL, Smith JW (2012b) Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells. Pigment Cell Melanoma Res 25(3):375–383.  https://doi.org/10.1111/j.1755-148X.2012.00989.xCrossRefPubMedPubMedCentralGoogle Scholar
  19. Flier JS, Mueckler MM, Usher P, Lodish HF (1987) Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 235(4795):1492–1495CrossRefGoogle Scholar
  20. Garcia-Cao I, Song MS, Hobbs RM, Laurent G, Giorgi C, de Boer VC, Anastasiou D, Ito K, Sasaki AT, Rameh L, Carracedo A, Vander Heiden MG, Cantley LC, Pinton P, Haigis MC, Pandolfi PP (2012) Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell 149(1):49–62.  https://doi.org/10.1016/j.cell.2012.02.030CrossRefPubMedPubMedCentralGoogle Scholar
  21. Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12(12):931–947.  https://doi.org/10.1038/nrd4002CrossRefPubMedGoogle Scholar
  22. Haq R, Shoag J, Andreu-Perez P, Yokoyama S, Edelman H, Rowe GC, Frederick DT, Hurley AD, Nellore A, Kung AL, Wargo JA, Song JS, Fisher DE, Arany Z, Widlund HR (2013) Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell 23(3):302–315.  https://doi.org/10.1016/j.ccr.2013.02.003CrossRefPubMedPubMedCentralGoogle Scholar
  23. Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C, Lee KC, Yung KY, Brenner D, Knobbe-Thomsen CB, Cox MA, Elia A, Berger T, Cescon DW, Adeoye A, Brustle A, Molyneux SD, Mason JM, Li WY, Yamamoto K, Wakeham A, Berman HK, Khokha R, Done SJ, Kavanagh TJ, Lam CW, Mak TW (2015) Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27(2):211–222.  https://doi.org/10.1016/j.ccell.2014.11.019CrossRefPubMedGoogle Scholar
  24. Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B, Matsuda M, Larkin J, Marais R, Sahai E (2015) Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling. Cancer Cell 27(4):574–588.  https://doi.org/10.1016/j.ccell.2015.03.008CrossRefPubMedPubMedCentralGoogle Scholar
  25. Israelsen WJ, Vander Heiden MG (2015) Pyruvate kinase: function, regulation and role in cancer. Semin Cell Dev Biol 43:43–51.  https://doi.org/10.1016/j.semcdb.2015.08.004CrossRefPubMedPubMedCentralGoogle Scholar
  26. Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, Kafri R, Kirschner MW, Clish CB, Mootha VK (2012) Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336(6084):1040–1044.  https://doi.org/10.1126/science.1218595CrossRefPubMedPubMedCentralGoogle Scholar
  27. Jiang P, Du W, Mancuso A, Wellen KE, Yang X (2013) Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493(7434):689–693.  https://doi.org/10.1038/nature11776CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kamphorst JJ, Cross JR, Fan J, de Stanchina E, Mathew R, White EP, Thompson CB, Rabinowitz JD (2013) Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci U S A 110(22):8882–8887.  https://doi.org/10.1073/pnas.1307237110CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kang HB, Fan J, Lin R, Elf S, Ji Q, Zhao L, Jin L, Seo JH, Shan C, Arbiser JL, Cohen C, Brat D, Miziorko HM, Kim E, Abdel-Wahab O, Merghoub T, Frohling S, Scholl C, Tamayo P, Barbie DA, Zhou L, Pollack BP, Fisher K, Kudchadkar RR, Lawson DH, Sica G, Rossi M, Lonial S, Khoury HJ, Khuri FR, Lee BH, Boggon TJ, He C, Kang S, Chen J (2015) Metabolic rewiring by oncogenic BRAF V600E links ketogenesis pathway to BRAF-MEK1 signaling. Mol Cell 59(3):345–358.  https://doi.org/10.1016/j.molcel.2015.05.037CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kaplon J, Zheng L, Meissl K, Chaneton B, Selivanov VA, Mackay G, van der Burg SH, Verdegaal EM, Cascante M, Shlomi T, Gottlieb E, Peeper DS (2013) A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498(7452):109–112.  https://doi.org/10.1038/nature12154CrossRefPubMedGoogle Scholar
  31. Kardos GR, Wastyk HC, Robertson GP (2015) Disruption of proline synthesis in melanoma inhibits protein production mediated by the GCN2 pathway. Mol Cancer Res 13(10):1408–1420.  https://doi.org/10.1158/1541-7786.MCR-15-0048CrossRefPubMedPubMedCentralGoogle Scholar
  32. Keith B, Johnson RS, Simon MC (2012) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12(1):9–22.  https://doi.org/10.1038/nrc3183CrossRefGoogle Scholar
  33. Kluza J, Corazao-Rozas P, Touil Y, Jendoubi M, Maire C, Guerreschi P, Jonneaux A, Ballot C, Balayssac S, Valable S, Corroyer-Dulmont A, Bernaudin M, Malet-Martino M, de Lassalle EM, Maboudou P, Formstecher P, Polakowska R, Mortier L, Marchetti P (2012) Inactivation of the HIF-1alpha/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants. Cancer Res 72(19):5035–5047.  https://doi.org/10.1158/0008-5472.CAN-12-0979CrossRefPubMedGoogle Scholar
  34. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24(22):2463–79CrossRefGoogle Scholar
  35. LaGory EL, Giaccia AJ (2016) The ever-expanding role of HIF in tumour and stromal biology. Nat Cell Biol 18(4):356–365.  https://doi.org/10.1038/ncb3330CrossRefPubMedPubMedCentralGoogle Scholar
  36. Lakhter AJ, Hamilton J, Konger RL, Brustovetsky N, Broxmeyer HE, Naidu SR (2016) Glucose-independent acetate metabolism promotes melanoma cell survival and tumor growth. J Biol Chem.  https://doi.org/10.1074/jbc.M115.712166CrossRefGoogle Scholar
  37. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293.  https://doi.org/10.1016/j.cell.2012.03.017CrossRefPubMedPubMedCentralGoogle Scholar
  38. Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, Karlsson C, Dalin MG, Akyurek LM, Lindahl P, Nilsson J, Bergo MO (2015) Antioxidants can increase melanoma metastasis in mice. Sci Transl Med 7(308):308re308.  https://doi.org/10.1126/scitranslmed.aad3740CrossRefGoogle Scholar
  39. LeBleu VS, O'Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, de Carvalho FM, Damascena A, Domingos Chinen LT, Rocha RM, Asara JM, Kalluri R (2014) PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16(10):992–1003., , 1001–1015.  https://doi.org/10.1038/ncb3039CrossRefPubMedPubMedCentralGoogle Scholar
  40. Lee AC, Fenster BE, Ito H, Takeda K, Bae NS, Hirai T, Yu ZX, Ferrans VJ, Howard BH, Finkel T (1999) Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J Biol Chem 274(12):7936–7940CrossRefGoogle Scholar
  41. Lim JH, Luo C, Vazquez F, Puigserver P (2014) Targeting mitochondrial oxidative metabolism in melanoma causes metabolic compensation through glucose and glutamine utilization. Cancer Res 74(13):3535–3545.  https://doi.org/10.1158/0008-5472.CAN-13-2893-TCrossRefPubMedGoogle Scholar
  42. Liu W, Beck BH, Vaidya KS, Nash KT, Feeley KP, Ballinger SW, Pounds KM, Denning WL, Diers AR, Landar A, Dhar A, Iwakuma T, Welch DR (2014) Metastasis suppressor KISS1 seems to reverse the Warburg effect by enhancing mitochondrial biogenesis. Cancer Res 74(3):954–963.  https://doi.org/10.1158/0008-5472.CAN-13-1183CrossRefPubMedGoogle Scholar
  43. Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, Vander Heiden MG (2011) Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 43(9):869–874.  https://doi.org/10.1038/ng.890CrossRefPubMedPubMedCentralGoogle Scholar
  44. Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G, Lazova R, Klump V, Pawelek JM, Xu X, Xu W, Schuchter LM, Davies MA, Herlyn M, Winkler J, Koumenis C, Amaravadi RK (2014) Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest 124(3):1406–1417.  https://doi.org/10.1172/JCI70454CrossRefPubMedPubMedCentralGoogle Scholar
  45. Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden KH (2013) Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493(7433):542–546.  https://doi.org/10.1038/nature11743CrossRefPubMedGoogle Scholar
  46. Maes H, Kuchnio A, Peric A, Moens S, Nys K, De Bock K, Quaegebeur A, Schoors S, Georgiadou M, Wouters J, Vinckier S, Vankelecom H, Garmyn M, Vion AC, Radtke F, Boulanger C, Gerhardt H, Dejana E, Dewerchin M, Ghesquiere B, Annaert W, Agostinis P, Carmeliet P (2014) Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 26(2):190–206.  https://doi.org/10.1016/j.ccr.2014.06.025CrossRefPubMedGoogle Scholar
  47. Mashimo T, Pichumani K, Vemireddy V, Hatanpaa KJ, Singh DK, Sirasanagandla S, Nannepaga S, Piccirillo SG, Kovacs Z, Foong C, Huang Z, Barnett S, Mickey BE, DeBerardinis RJ, Tu BP, Maher EA, Bachoo RM (2014) Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159(7):1603–1614.  https://doi.org/10.1016/j.cell.2014.11.025CrossRefPubMedPubMedCentralGoogle Scholar
  48. Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ (2012) Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481(7381):385–388.  https://doi.org/10.1038/nature10642CrossRefGoogle Scholar
  49. Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF (2010) Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140(1):49–61.  https://doi.org/10.1016/j.cell.2009.11.027CrossRefPubMedPubMedCentralGoogle Scholar
  50. Nowicki S, Gottlieb E (2015) Oncometabolites: tailoring our genes. FEBS J 282(15):2796–2805.  https://doi.org/10.1111/febs.13295CrossRefPubMedPubMedCentralGoogle Scholar
  51. Parmenter TJ, Kleinschmidt M, Kinross KM, Bond ST, Li J, Kaadige MR, Rao A, Sheppard KE, Hugo W, Pupo GM, Pearson RB, McGee SL, Long GV, Scolyer RA, Rizos H, Lo RS, Cullinane C, Ayer DE, Ribas A, Johnstone RW, Hicks RJ, McArthur GA (2014) Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov.  https://doi.org/10.1158/2159-8290.CD-13-0440CrossRefGoogle Scholar
  52. Pinheiro C, Miranda-Goncalves V, Longatto-Filho A, Vicente AL, Berardinelli GN, Scapulatempo-Neto C, Costa RF, Viana CR, Reis RM, Baltazar F, Vazquez VL (2016) The metabolic microenvironment of melanomas: prognostic value of MCT1 and MCT4. Cell Cycle 15(11):1462–1470.  https://doi.org/10.1080/15384101.2016.1175258CrossRefPubMedPubMedCentralGoogle Scholar
  53. Pisarsky L, Bill R, Fagiani E, Dimeloe S, Goosen RW, Hagmann J, Hess C, Christofori G (2016) Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep 15(6):1161–1174.  https://doi.org/10.1016/j.celrep.2016.04.028CrossRefPubMedPubMedCentralGoogle Scholar
  54. Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z (2015) Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527(7577):186–91CrossRefGoogle Scholar
  55. Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, Salem G, Pohida T, Heenan P, Duray P, Kallioniemi O, Hayward NK, Trent JM, Meltzer PS (2003) High frequency of BRAF mutations in nevi. Nat Genet 33(1):19–20.  https://doi.org/10.1038/ng1054CrossRefPubMedPubMedCentralGoogle Scholar
  56. Rohrig F, Schulze A (2016) The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer.  https://doi.org/10.1038/nrc.2016.89CrossRefGoogle Scholar
  57. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO (2014) Antioxidants accelerate lung cancer progression in mice. Sci Transl Med 6(221):221ra215.  https://doi.org/10.1126/scitranslmed.3007653CrossRefGoogle Scholar
  58. Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, Goodwin LM, Smethurst E, Mason S, Blyth K, McGarry L, James D, Shanks E, Kalna G, Saunders RE, Jiang M, Howell M, Lassailly F, Thin MZ, Spencer-Dene B, Stamp G, van den Broek NJ, Mackay G, Bulusu V, Kamphorst JJ, Tardito S, Strachan D, Harris AL, Aboagye EO, Critchlow SE, Wakelam MJ, Schulze A, Gottlieb E (2015) Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27(1):57–71.  https://doi.org/10.1016/j.ccell.2014.12.002CrossRefPubMedPubMedCentralGoogle Scholar
  59. Scott DA, Richardson AD, Filipp FV, Knutzen CA, Chiang GG, Ronai ZA, Osterman AL, Smith JW (2011) Comparative metabolic flux profiling of melanoma cell lines: beyond the Warburg effect. J Biol Chem 286(49):42626–42634.  https://doi.org/10.1074/jbc.M111.282046CrossRefPubMedPubMedCentralGoogle Scholar
  60. Seguin F, Carvalho MA, Bastos DC, Agostini M, Zecchin KG, Alvarez-Flores MP, Chudzinski-Tavassi AM, Coletta RD, Graner E (2012) The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas. Br J Cancer 107(6):977–987.  https://doi.org/10.1038/bjc.2012.355CrossRefPubMedPubMedCentralGoogle Scholar
  61. Sheen JH, Zoncu R, Kim D, Sabatini DM (2011) Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell 19(5):613–628.  https://doi.org/10.1016/j.ccr.2011.03.012CrossRefPubMedPubMedCentralGoogle Scholar
  62. Shin S, Buel GR, Wolgamott L, Plas DR, Asara JM, Blenis J, Yoon SO (2015) ERK2 mediates metabolic stress response to regulate cell fate. Mol Cell 59(3):382–398.  https://doi.org/10.1016/j.molcel.2015.06.020CrossRefPubMedPubMedCentralGoogle Scholar
  63. Shoag J, Haq R, Zhang M, Liu L, Rowe GC, Jiang A, Koulisis N, Farrel C, Amos CI, Wei Q, Lee JE, Zhang J, Kupper TS, Qureshi AA, Cui R, Han J, Fisher DE, Arany Z (2012) PGC-1 coactivators regulate MITF and the tanning response. Mol Cell. S1097-2765(12)00908-2 [pii].  https://doi.org/10.1016/j.molcel.2012.10.027CrossRefGoogle Scholar
  64. Slominski A, Kim TK, Brozyna AA, Janjetovic Z, Brooks DL, Schwab LP, Skobowiat C, Jozwicki W, Seagroves TN (2014) The role of melanogenesis in regulation of melanoma behavior: melanogenesis leads to stimulation of HIF-1alpha expression and HIF-dependent attendant pathways. Arch Biochem Biophys 563:79–93.  https://doi.org/10.1016/j.abb.2014.06.030CrossRefPubMedPubMedCentralGoogle Scholar
  65. Sporn MB, Liby KT (2012) NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer 12(8):564–571.  https://doi.org/10.1038/nrc3278CrossRefPubMedGoogle Scholar
  66. Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, Sugano S, Sato E, Nagao T, Yokote K, Tatsuno I, Prives C (2010) Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S A 107(16):7461–7466.  https://doi.org/10.1073/pnas.1002459107CrossRefPubMedPubMedCentralGoogle Scholar
  67. Telang S, Yalcin A, Clem AL, Bucala R, Lane AN, Eaton JW, Chesney J (2006) Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene 25(55):7225–7234.  https://doi.org/10.1038/sj.onc.1209709CrossRefPubMedGoogle Scholar
  68. Vander Heiden MG (2011) Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 10(9):671–684.  https://doi.org/10.1038/nrd3504CrossRefPubMedGoogle Scholar
  69. Vander Heiden MG, Lunt SY, Dayton TL, Fiske BP, Israelsen WJ, Mattaini KR, Vokes NI, Stephanopoulos G, Cantley LC, Metallo CM, Locasale JW (2011) Metabolic pathway alterations that support cell proliferation. Cold Spring Harb Symp Quant Biol 76:325–334.  https://doi.org/10.1101/sqb.2012.76.010900. sqb.2012.76.010900 [pii]CrossRefPubMedGoogle Scholar
  70. Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, Clish CB, Granter SR, Widlund HR, Spiegelman BM, Puigserver P (2013) PGC1alpha expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23(3):287–301.  https://doi.org/10.1016/j.ccr.2012.11.020CrossRefPubMedPubMedCentralGoogle Scholar
  71. Vredeveld LC, Possik PA, Smit MA, Meissl K, Michaloglou C, Horlings HM, Ajouaou A, Kortman PC, Dankort D, McMahon M, Mooi WJ, Peeper DS (2012) Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis. Genes Dev 26(10):1055–1069.  https://doi.org/10.1101/gad.187252.112CrossRefPubMedPubMedCentralGoogle Scholar
  72. Wang Q, Beaumont KA, Otte NJ, Font J, Bailey CG, van Geldermalsen M, Sharp DM, Tiffen JC, Ryan RM, Jormakka M, Haass NK, Rasko JE, Holst J (2014) Targeting glutamine transport to suppress melanoma cell growth. Int J Cancer.  https://doi.org/10.1002/ijc.28749CrossRefGoogle Scholar
  73. Warburg O (1924) On the metabolism of cancer cells. Naturwissenschaften 12:1131–1137CrossRefGoogle Scholar
  74. Warita K, Warita T, Beckwitt CH, Schurdak ME, Vazquez A, Wells A, Oltvai ZN (2014) Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal-like cancer cells that lack functional E-cadherin mediated cell cohesion. Sci Rep 4:7593.  https://doi.org/10.1038/srep07593CrossRefPubMedPubMedCentralGoogle Scholar
  75. Wawrzyniak JA, Bianchi-Smiraglia A, Bshara W, Mannava S, Ackroyd J, Bagati A, Omilian AR, Im M, Fedtsova N, Miecznikowski JC, Moparthy KC, Zucker SN, Zhu Q, Kozlova NI, Berman AE, Hoek KS, Gudkov AV, Shewach DS, Morrison CD, Nikiforov MA (2013) A purine nucleotide biosynthesis enzyme guanosine monophosphate reductase is a suppressor of melanoma invasion. Cell Rep 5(2):493–507.  https://doi.org/10.1016/j.celrep.2013.09.015CrossRefPubMedPubMedCentralGoogle Scholar
  76. White E (2012) Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 12(6):401–410.  https://doi.org/10.1038/nrc3262CrossRefPubMedPubMedCentralGoogle Scholar
  77. Xie X, Koh JY, Price S, White E, Mehnert JM (2015) Atg7 overcomes senescence and promotes growth of BrafV600E-driven melanoma. Cancer Discov 5(4):410–423.  https://doi.org/10.1158/2159-8290.CD-14-1473CrossRefPubMedPubMedCentralGoogle Scholar
  78. Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH, Bosenberg MW, McMahon M, Cantley LC, Zheng B (2013) Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci U S A 110(45):18226–18231.  https://doi.org/10.1073/pnas.1317577110CrossRefPubMedPubMedCentralGoogle Scholar
  79. Zelenay S, van der Veen AG, Bottcher JP, Snelgrove KJ, Rogers N, Acton SE, Chakravarty P, Girotti MR, Marais R, Quezada SA, Sahai E, Reis ESC (2015) Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162(6):1257–1270.  https://doi.org/10.1016/j.cell.2015.08.015CrossRefPubMedPubMedCentralGoogle Scholar
  80. Zhang J, Fan J, Venneti S, Cross JR, Takagi T, Bhinder B (2014) Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol Cell 56(2):205–18CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Franziska Baenke
    • 1
  • Nathalie Dhomen
    • 1
  • Eyal Gottlieb
    • 2
  • Richard Marais
    • 1
    Email author
  1. 1.Molecular Oncology Laboratory, Cancer Research UK Manchester InstituteThe University of ManchesterManchesterUK
  2. 2.Cancer Metabolism, Rappaport Faculty of Medicine, Technion Israel Institute of TechnologyHaifaIsrael

Section editors and affiliations

  • David E. Fisher
    • 1
  • Nick Hayward
    • 2
  • David C. Whiteman
    • 3
  • Keith T. Flaherty
    • 4
  • F. Stephen Hodi
    • 5
    • 6
  • Hensin Tsao
    • 7
    • 8
  • Glenn Merlino
    • 9
  1. 1.Department of Dermatology, Harvard/MGH Cutaneous Biology Research Center, and Melanoma Program, MGH Cancer CenterMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  2. 2.QIMR Berghofer Medical Research InstituteHerstonAustralia
  3. 3.QIMR Berghofer Medical Research InstituteHerstonAustralia
  4. 4.Henri and Belinda Termeer Center for Targeted TherapiesMGH Cancer CenterBostonUSA
  5. 5.FraminghamUSA
  6. 6.Department of Medicine, Brigham and Women's HospitalDana-Farber Cancer InstituteBostonUSA
  7. 7.AuburndaleUSA
  8. 8.Harvard-MIT Health Sciences and TechnologyCambridgeUSA
  9. 9.Center for Cancer ResearchNational Cancer InstituteBethesdaUSA

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