Lipid metabolism in cancer: New perspectives and emerging mechanisms

Tumors undergo metabolic transformations to sustain uncontrolled proliferation, avoid cell death, and seed in secondary organs. An increased focus on cancer lipid metabolism has unveiled a number of mechanisms that promote tumor growth survival, many which are independent classical cellular bioenergetics. These include modulation ferroptotic-mediated support during metastasis, interactions with the cells microenvironment. As such, targeting for anti-cancer therapies is attractive, recent work small-molecule inhibitors identifying compounds target metabolism. Here, we discuss these topics identify open questions. Altered energetics well-established hallmark (Hanahan Weinberg, 2011Hanahan D. Weinberg R.A. Hallmarks cancer: next generation.Cell. 2011; 144: 646-674Abstract Full Text PDF PubMed Scopus (35892) Google Scholar). Multiple pathways, mechanisms, proteins involved changing how utilize different metabolites molecules aberrant replication, dissemination from primary tumor, establishment, immune evasion. Lipid often drastically altered undergoing transformation malignant phenotype. Tumor can increase de novo lipogenesis, fatty acid (FA) uptake, FA oxidation (FAO) energy production accumulation. The canonical rationale elevated lipids required plasma membrane synthesis production. However, it now well known play multiple other roles within For example, oncogenic signaling pathways (including B-Raf kinase [BRAF] epidermal factor receptor [EGFR]) drive dysregulated metabolism, influencing composition saturation modulate tolerance reactive oxygen species (ROS) survival (Bi et al., 2019Bi J. Ichu T.A. Zanca C. Yang H. Zhang W. Gu Y. Chowdhry S. Reed A. Ikegami Turner K.M. al.Oncogene amplification renders cancers dependent remodeling.Cell Metab. 2019; 30: 525-538.e8Abstract (44) Scholar; Gimple 2019Gimple R.C. Kidwell R.L. Kim L.J.Y. Sun T. Gromovsky A.D. Wu Q. Wolf M. Lv Bhargava Jiang L. al.Glioma stem cell–specific superenhancer promotes polyunsaturated fatty-acid EGFR signaling.Cancer Discov. 9: 1248-1267Crossref (22) Talebi 2018Talebi Dehairs Rambow F. Rogiers Nittner Derua R. Vanderhoydonc Duarte J.A.G. Bosisio Van Den Eynde K. al.Sustained SREBP-1-dependent lipogenesis as key mediator resistance BRAF-targeted therapy.Nat. Commun. 2018; 2500Crossref (27) Recent finds changes enable invasion stimulate downstream signaling, regulate oxidative stress, provide fuel various stress situations (Ladanyi 2018Ladanyi Mukherjee Kenny H.A. Johnson Mitra A.K. Sundaresan Nieman Pascual G. Benitah S.A. Montag al.Adipocyte-induced CD36 expression drives ovarian progression metastasis.Oncogene. 37: 2285-2301Crossref (96) Mullen 2016Mullen P.J. Yu Longo Archer M.C. Penn L.Z. interplay between signalling mevalonate pathway cancer.Nat. Rev. Cancer. 2016; 16: 718-731Crossref (170) 2017Pascual Avgustinova Mejetta Martín Castellanos Attolini C.S.-O. Berenguer Prats N. Toll Hueto J.A. al.Targeting metastasis-initiating through CD36.Nature. 2017; 541: 41-45Crossref (510) Röhrig Schulze, 2016Röhrig Schulze multifaceted 732-749Crossref (448) Slebe 2016Slebe Rojo Vinaixa García-Rocha Testoni Guiu Planet E. Samino Arenas E.J. Beltran al.FoxA LIPG endothelial lipase control uptake extracellular breast growth.Nat. 7: 11199Crossref (32) While lead endoplasmic reticulum (ER) apoptosis (Ackerman Simon, 2014Ackerman Simon Hypoxia, lipids, surviving harsh microenvironment.Trends Cell Biol. 2014; 24: 472-478Abstract (256) Scholar), high amounts (PUFA) sensitize peroxidation ferroptosis, recently identified form non-apoptotic, iron- PUFA-dependent death (Dixon 2012Dixon S.J. Lemberg Lamprecht M.R. Skouta Zaitsev E.M. Gleason C.E. Patel D.N. Bauer A.J. Cantley A.M. W.S. al.Ferroptosis: an iron-dependent nonapoptotic death.Cell. 2012; 149: 1060-1072Abstract (2889) Doll 2017Doll Proneth B. Tyurina Y.Y. Panzilius Kobayashi Ingold I. Irmler Beckers Aichler Walch al.ACSL4 dictates ferroptosis sensitivity by shaping composition.Nat. Chem. 13: 91-98Crossref (655) Friedmann Angeli 2019aFriedmann J.P. Miyamoto Ferroptosis: greasy side death.Chem. Res. Toxicol. 32: 362-369Crossref (17) Stockwell, 2016Yang Stockwell B.R. peroxidation.Trends 26: 165-176Abstract (451) Further, exposure high-fat diets (HFDs) interact development ways. findings suggest HFD change normal liver similar found hepatocellular carcinoma (HCC) this may prime tissue carcinogenesis (Broadfield 2021Broadfield L.A. Schmieder Veys Vriens Karasawa Fujita Fujii Eto Holvoet Vangoitsenhoven al.Fat induces glucose non-transformed tumorigenesis Working title : fat metabolization.Cancer 2021; https://doi.org/10.1158/0008-5472.CAN-20-1954Crossref (3) In review, highlighting driving our understanding non-canonical functions their cell. crosstalk microenvironment (TME) strongly impact hallmarks, mediators such prostaglandin E2 (PGE2) lysophosphatidic (LPA). define stimulating tumor-promoting inflammation (Chiurchiù 2018Chiurchiù V. Leuti Maccarrone Bioactive chronic inflammation: managing fire within.Front. Immunol. 38Crossref (143) enhancing angiogenesis (Hisano Hla, 2019Hisano Hla lysolipids angiogenesis.Pharmacol. Ther. 193: (35) stromal cells, even allowing escape system affecting compartment (Baek 2017Baek A.E. Y.-R.A. He Wardell S.E. Chang C.Y. Kwon Pillai R.V. McDowell H.B. Thompson J.W. Dubois L.G. al.The cholesterol metabolite 27 hydroxycholesterol facilitates metastasis its actions cells.Nat. 8: 864Crossref (139) Zelenay 2015Zelenay Der Veen A.G. Böttcher Snelgrove K.J. Rogers Acton Chakravarty P. Girotti Marais Quezada al.Cyclooxygenase-dependent evasion immunity.Cell. 2015; 162: 1257-1270Abstract (523) will components TME, including tumor-associated cells. Finally, after outlining progression, have therapeutic targets opportunities further development. We ongoing under pre-clinical clinical investigation. goal largely enhance current treatment protocols, acting adjuvant treatments. summarize inhibitors, be targeted immunometabolism. De process typically occurs adipocytes hepatocytes (Figure 1). not all synthesized novo; alpha-linolenic (ALA) linoleic (LA) essential FAs humans mammals. must consumed diet taken up use Lipids local brought across membranes via diffusion, transport proteins, translocase/CD36. Alternatively, low- very-low-density lipoproteins (LDLs VLDLs, respectively) (Guan 2019Guan X. Liu Z. Zhao Tao Yuan Wang Ding Emerging low-density lipoprotein cancer.Lipids Health Dis. 18: 137Crossref (7) Lupien 2020Lupien L.E. Bloch Traphagen N.A. Feng W.W. Davis W.L. Dennis Swinnen J.V. Wells W.A. Smits N.C. al.Endocytosis very lipoproteins: unexpected mechanism acquisition cells.J. 2020; 61: 205-218Abstract (6) citrate starting point, where ATP-citrate lyase (ACLY) converts acetyl-CoA oxaloacetate. Cytosolic pools supported TCA cycle or glutamine reductive carboxylation acetate bypass requirement citrate, directly contributing cytosolic synthetases, synthetase 2 (ACSS2) (Pietrocola 2015Pietrocola Galluzzi Bravo-San Pedro J.M. Madeo Kroemer Acetyl coenzyme A: central second messenger.Cell 21: 805-821Abstract Acetyl-CoA carboxylases 1 (ACACA ACACB, then generate malonyl-CoA rate-limiting step lipogenesis. synthase (FASN) generates carbon chains adding molecules, eventually producing palmitate (16:0). Palmitate highly abundant saturated FA. It modified stearoyl-CoA desaturase (SCD) (FADS2) monounsaturated (MUFA) palmitoleate sapienate, respectively (Vriens 2019Vriens Christen Parik Broekaert Yoshinaga Escalona-Noguero Cornfield al.Evidence alternative desaturation increasing plasticity.Nature. 566: 403-406Crossref (128) Elongation reactions chain length elongation very-long-chain (ELOVL enzymes). PUFA generated (ALA LA); however, rate conversion well-known bioactive species, eicosapentaenoic (EPA, 22:5n3) docosahexaenoic (DHA, 22:6n3) quite low (Burdge Calder, 2005Burdge G.C. Calder P.C. Conversion ?-linolenic longer-chain acids human adults.Reprod. Nutr. Dev. 2005; 45: 581-597Crossref (0) Additional classes, phospholipids, combining common backbone. Phospholipids phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), building blocks bilayer membranes. Glycerol another backbone used diacylglycerols (DAGs) triacylglycerols (TAGs). Glycerol-3-phosphate acyltransferase (GPAT) acylglycerophosphate acyltransferase/lysophosphatidic (AGPAT/LPAAT) produce DAG LPA phosphatidic (PA) intermediates Diacylglycerol acyltransferases (DGAT) add additional FA-CoA TAG species. TAGs main storage sequestered droplets (LDs), phospholipid enveloped vesicles store release lipids. Lipase enzymes, (LPL), hydrolyze free (FFAs). Degradation intracellular initiated adipose triglyceride (ATGL), hydrolyzing DAG, hydrolyzed hormone-sensitive (HSL), monoacylglycerol (MAG) MAG (MGL) hydrolyzes glycerol backbone, freeing classically described source FAO mitochondria. Carnitine palmitoyltransferase (CPT) enzyme mitochondrial long-chain FA, mediating into Once inside matrix, available trifunctional protein (MTP), breaking down entry cofactors NADH FADH2 electron ATP phosphorylation. way, produces Cholesterol type critical structures. also converted acetoacetyl-CoA acetyltransferase (ACAT). 3-hydroxy-3-methylglutaryl (HMG)-CoA condensation HMG-CoA (HMGCS). reductase (HMGCR) synthesis, Mevalonate, like palmitate, modifications variety biological uses cell, biogenesis. To tumors adaptable, them thrive most adverse conditions. This plasticity manifested phenotypes shaped genetic epigenetic alterations, affected characteristics nutrient availability, pH levels, interaction (Strickaert 2017Strickaert Saiselet Dom Deken Dumont J.E. Feron O. Sonveaux Maenhaut Cancer heterogeneity compatible one unique map.Oncogene. 36: 2637-2642Crossref (39) Within adaptations, reprogramming plays role promoting (Beloribi-Djefaflia 2016Beloribi-Djefaflia Vasseur Guillaumond cells.Oncogenesis. 5: e189Crossref show pronounced alterations signatures. upregulation alteration cancer. provides phospholipids proliferation but allows important certain (Röhrig documented phenomenon achieved lipogenic enzymes. example ACLY, activity lung (Migita 2008Migita Narita Nomura Miyagi Inazuka Matsuura Ushijima Mashima Seimiya Satoh al.ATP lyase: activation implications non-small cancer.Cancer 2008; 68: 8547-8554Crossref (245) Scholar) upregulated HCC vivo murine model (Calvisi 2011Calvisi D.F. Ho Ladu Lee Mattu Destefanis Delogu Zimmermann Ericsson al.Increased induced AKT-mTORC1-RPS6 carcinoma.Gastroenterology. 140: 1071-1083Abstract (274) ACSS2 been reported cancer, supporting synthesis. correlated poorer prognosis expressed glioblastoma, breast, ovarian, (Schug 2016Schug Z.T. Vande Voorde Gottlieb fate 708-717Crossref ACACA Nelson 2017Nelson M.E. Lahiri Chow J.D.Y. Byrne F.L. Hargett S.R. Breen D.S. Olzomer Cooney G.J. al.Inhibition hepatic enhances antioxidant defence survival.Nat. 14689Crossref (23) clear renal (ccRCC) (Cancer Genome Atlas Research Network, 2013Cancer NetworkComprehensivemolecular characterization carcinoma.Nature. 2013; 499: 43-49Crossref Moreover, FASN years several types (Kuhajda 1994Kuhajda F.P. Jenner Wood F.D. Hennigar Jacobs L.B. Dick J.D. Pasternack G.R. Fatty synthesis: A potential selective antineoplastic therapy.Proc. Natl. Acad. Sci. USA. 1994; 91: 6379-6383Crossref (534) Ricoult 2016Ricoult S.J.H. Yecies J.L. Ben-Sahra Manning B.D. Oncogenic PI3K K-Ras mTORC1 SREBP.Oncogene. 35: 1250-1260Crossref (74) prostate (Swinnen 2002Swinnen Roskams Joniau Poppel Oyen Baert Heyns Verhoeven Overexpression early event cancer.Int. 2002; 98: 19-22Crossref (283) ccRCC gliomas (Tao 2013Tao B.B. Shi X.-H. C.-L. Li W.-Q. Dong Hu G.-H. Hou L.-J. Luo al.Up-regulation USP2a correlates glioma grade.J. Clin. Neurosci. 20: 717-720Abstract Furthermore, was associated higher grade importance phenotype transformed Overall, enzymes feature among caner types. affect maintained balance. degree unsaturation balance, level matter life 2019bFriedmann Krysko D.V. Conrad Ferroptosis at crossroads cancer-acquired drug evasion.Nat. 19: 405-414Crossref (61) Rysman 2010Rysman Brusselmans Scheys Timmermans Munck Veldhoven P.P. Waltregny Daniëls V.W. Machiels al.De protects radicals chemotherapeutics saturation.Cancer 2010; 70: 8117-8126Crossref (369) instance, SCD mono-unsaturation overexpression correlate decreased (Peck 2016Peck – cancer?.FEBS 283: 2767-2778Crossref Since reaction catalyzed requires molecular oxygen, hampered hypoxic conditions, consideration solid disordered vascularization. glioblastoma lines, serum limitations viability, effect rescued addition MUFA oleic (Young 2013Young R.M. Ackerman Quinn Z.L. Mancuso Gruber Giannoukos Bobrovnikova-Marjon Diehl Keith Dysregulated critically desaturated tumor-like stress.Genes 27: 1115-1131Crossref (107) SCD1 inhibitor phenocopied O2 deprivation, state oleate, evidencing unsaturated nutrients hypoxia Human cervical, lines were shown compensate environments scavenging vitro (Kamphorst 2013Kamphorst J.J. Cross J.R. Fan Stanchina Mathew White E.P. C.B. Rabinowitz Hypoxic Ras-transformed lysophospholipids.Proc. 110: 8882-8887Crossref (374) aside regulating upregulate response (Lewis 2015Lewis C.A. Brault Peck Bensaad Griffiths Mitter East Dankworth Alibhai al.SREBP maintains biosynthesis viability lipid- oxygen-deprived conditions defines gene signature poor multiforme.Oncogene. 34: 5128-5140Crossref (65) lipid-depleted microenvironment, downregulation inhibition deficiency induce ER line (Griffiths 2013Griffiths Lewis Ros Ferber E.C. Konisti Miess al.Sterol regulatory element binding protein-dependent regulation supports growth.Cancer 1: 3Crossref SREBP, major regulator balancing study employing showed loss SREBP impaired uncoupling (Williams 2013Williams Argus Zhu Wilks M.Q. Marbois B.N. York Kidani Pourzia A.L. Akhavan Lisiero al.An SCAP/SREBP axis protect lipotoxicity.Cancer 73: 2850-2862Crossref (93) maintained, capacity lost due decrease activity, generating imbalance (SFA) causing lipotoxicity excessive accumulation non-adipose dysfunction (Han Kaufman, 2016Han Kaufman R.J. lipotoxicity.J. 57: 1329-1338Abstract (169) oleate supplementation restored knockdown effects indicating contrast, resistant inhibition, finding (liver, lung, prostate), some mouse HCCs carcinomas FADS2 enzyme, necessary convert ?-linoleic arachidonic (AA; definitions abbreviations, (Box 1)) (Zhang 2016Zhang J.Y. Kothapalli K.S.D. Brenna J.T. Desaturase elongase-limiting endogenous polyunsat