Lipid metabolism in malignant tumor brain metastasis: reprogramming and therapeutic potential

ABSTRACTIntroduction Brain metastasis is a highly traumatic event in the progression of malignant tumors, often symbolizing higher mortality. Metabolic alterations are hallmarks of cancer, and the mask of lipid metabolic program rearrangement in cancer progression is gradually being unraveled.Areas covered In this work, we reviewed clinical and fundamental studies related to lipid expression and activity changes in brain metastases originating from lung, breast, and cutaneous melanomas, respectively. Novel roles of lipid metabolic reprogramming in the development of brain metastasis from malignant tumors were identified and its potential as a therapeutic target was evaluated. Published literature and clinical studies in databases consisting of PubMed, Embase, Scopus and www.ClinicalTrials.gov from 1990 to 2022 were searched.Expert opinion Lipid metabolic reprogramming in brain metastasis is involved in de novo lipid synthesis within low lipid availability environments, regulation of lipid uptake and storage, metabolic interactions between brain tumors and the brain microenvironment, and membrane lipid remodeling, in addition to being a second messenger for signal transduction. Although some lipid metabolism modulators work efficiently in preclinical models, there is still a long way to go from laboratory to clinic. This area of research holds assurance for the organ-targeted treatment of brain metastases through drug-regulated metabolic targets and dietary interventions.KEYWORDS: Brain metastasisde novo lipogenesisfatty acid synthaselipid metabolismmalignant tumormembrane lipid remodelingmicroenvironment Article highlights Lipid metabolic reprogramming in brain metastasis is involved in de novo lipid synthesis within low-lipid availability environments, regulation of lipid uptake and storage, metabolic interactions between brain tumors and the brain microenvironment, and membrane lipid remodeling, in addition to being a second messenger for signal transduction.The brain's low-lipid availability microenvironment selects 'seed' cells that can synthesize fatty acids on their own.De novo lipogenesis primarily affects the survival of cancer cells in the brain microenvironment but has a limited role in brain micro-metastasis formation.In addition to affecting membrane properties, the remodeling of membrane lipids affects the homeostasis of other metabolite classes and is associated with oxidative stress and ferroptosis.Preclinical studies targeting lipid metabolism have shown promising results in brain metastasis, offering novel therapeutic opportunities for brain metastasis.Abbreviations CNS=central nervous systemMRI=magnetic resonance imagingNSCLC=non-small cell lung cancerFA=fatty acidDNL=de novo lipogenesisACSS2=cytoplasmic acetyl-CoA synthetase 2TCA=tricarboxylic acidPUFAs=polyunsaturated fatty acidsDHA=docosahexaenoic acidBBB=blood-brain barrierPDX=patient-derived xenograftPM=Plasma membraneLPCAT1=lysophosphatidylcholine acyltransferases 1LPC=lysophosphatidylcholinePC=phosphatidylcholineEGFR=epidermal growth factor receptorPI3K=phosphoinositide 3-kinaseAKT=protein kinase BTAG=triacylglycerolsmTORC=mammalian target of rapamycin complexHer2=human epidermal growth factor receptor 2SREBP1=sterol regulatory-element binding proteins 1FASN=fatty acid synthaseSCD1=stearoyl coenzyme a desaturase 1ACLY=ATP citrate lyaseTNBC=triple-negative breast cancerNADPH=nicotinamide adenine dinucleotide phosphate hydrogenCSF=cerebrospinal fluidMFP=mammary fat padMUFAs=monounsaturated fatty acidsACC=acetyl-CoA carboxylaseFABP7=fatty acid binding protein 7BLBP=brain lipid binding proteinLDs=lipid dropletsOXPHOS=oxidative phosphorylationCD36=cluster of differentiation 36FABP6=fatty acid binding protein 6PPARγ=Peroxisome Proliferator-Activated receptor γCM=conditioned mediumAA=arachidonic acidPCDH7=protocadherin 7PLCβ=phospholipase CβCaMKII=calmodulin-dependent protein kinase IIPIP2=phosphatidylinositol 4,5-bisphosphateIP3=inositol 1,4,5-trisphosphateDAG=1,2-diacylglycerolER=endoplasmic reticulumPKC=protein kinase CFAO=fatty acid oxidationEMT=epithelial-mesenchymal transitionPET=positron emission tomographyPPMP=L-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanolDeclaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThis paper was not funded.