Metabolic adaptations in prostate cancer

REVIEW ARTICLE OPEN Cellula and Molecula Biology Me abolic adap a ions in p os a e cance Mikel Pujana-Vaque izo 1,2 , Lau a Bozal-Bas e a 1 ✉and A kai z Ca acedo 1,2,3,4,5 ✉ © The Au ho (s) 2024 P os a e cance is one o he mos commonly diagnosed cance s in men and is a majo cause o cance - ela ed dea hs wo ldwide. Among he molecula p ocesses ha con ibu e o his disease, he weigh o me abolism has been placed unde he limeligh in ecen yea s. Tumou s exhibi me abolic adap a ions o comply wi h hei biosyn he ic needs. Howe e , me aboli es also play an impo an ole in suppo ing cell su i al in challenging en i onmen s o emodelling he umou mic oen i onmen , hus being ecognized as a hallma k in cance . P os a e cance is uniquely d i en by and ogen ecep o signalling, and his knowledge has also influenced he pa hs o cance me abolism esea ch. This e iew p o ides a comp ehensi e pe spec i e on he me abolic adap a ions ha suppo p os a e cance p og ession beyond and ogen signalling, wi h a pa icula ocus on umou cell in insic and ex insic pa hways. B i ish Jou nal o Cance (2024) 131:1250–1262; h ps://doi.o g/10.1038/s41416-024-02762-z INTRODUCTION The and ogen ecep o (AR) is a cen al playe in he biology o he p os a e, ope a ing as a nuclea ecep o essen ial o no mal p os a e de elopmen and unc ion [1]. AR media es he e ec s o and ogens and egula es he exp ession o genes in ol ed in p os a e g ow h, main enance, and di e en ia ion. Beyond de elopmen al s ages, AR also influences p os a e heal h h oughou adul hood [2]. AR signalling is linked o he onse and p og ession o p os a e cance (PCa), whe e i becomes a p ima y d i e o umou g ow h. The e o e, inhibi ion o AR unc ion ep esen s he a ge ed he apy in his disease [3]. AR ep og ams PCa cellula me abolism, c ea ing a unique molecula scena io ha has been documen ed o he las 100 yea s [4]. Ne e heless, he complexi y unde lying cellula me abolism ex ends beyond AR signalling, which is en isioned o o e inno a i e he apeu ic oppo uni ies. Ou cu en unde s anding o cellula me abolism encompasses aspec s such as he umou mic oen i onmen (TME) o die . In his e iew, we will explo e majo me abolic pa hways suppo ing PCa p og ession and me as asis, wi h special emphasis on umou cell-in insic and ex insic glucose, lipid and one-ca bon me abolism (1 C me abo- lism), while o he ele an p ocesses including he connec ion be ween me abolism and epigene ics will be le ou o he scope o his wo k. Fu he mo e, we will inco po a e new e idence om o he umou ypes o iden i y sha ed cha ac e is ics ha can apply o PCa. MAJOR METABOLIC ALTERATIONS IN PROSTATE CANCER CELLS Glucose me abolism Glycolysis and he Wa bu g e ec . Glycolysis me abolises glucose o py u a e ia a se ies o in e media e eac ions, gene a ing ATP and NADH (Fig. 1). Cance cells o en exhibi inc eased glycoly ic ac i i y o gene a e lac a e, e en in he p esence o oxygen, known as ae obic glycolysis o he Wa bu g e ec [5]. Despi e i s lowe e ficiency compa ed o oxida i e phospho yla ion (OXPHOS) in he mi ochond ia, cance cells hea ily depend on his pa hway o p oduce ene gy. I is impo an o s a e ha he inc ease o anae obic glucose u ilisa ion does no imply a educ ion in mi ochond ial OXPHOS ac i i y, in con as o he ini ial hypo h- esis o D . O o Wa bu g [6]. Al hough se e al hypo heses ha e been p oposed, he eason why p oli e a ing cells me abolise glucose p edominan ly o p oduce lac a e emains elusi e. Two complemen a y publica ions a gue ha when he demand o NAD+exceeds he demand o ATP, esul ing in he sa u a ion o he mi ochond ial NADH, umou cells en o ce ae obic glycolysis e en in he p esence o oxygen [7,8]. These me abolic adap a ions ha e been b ough om bench o bedside h ough di e en app oaches. On he one hand, ae obic glycolysis esul s in an ele a ed demand o glucose, which has inspi ed he de elopmen o cance -moni o ing s a egies based on he up ake o 18 F-fluo odeoxyglucose wi h posi on emission omog aphy (PET) [9]. On he o he hand, al hough al e a ions in copy numbe Recei ed: 13 Ma ch 2024 Re ised: 7 June 2024 Accep ed: 11 June 2024 Published online: 5 July 2024 1 Cen e o Coope a i e Resea ch in Biosciences (CIC bioGUNE), Basque Resea ch and Technology Alliance (BRTA), Bizkaia Technology Pa k, Building 801A, 48160 De io, Spain. 2 Cen o de In es igación Biomédica En Red de Cánce (CIBERONC), 28029 Mad id, Spain. 3 T asla ional P os a e Cance Resea ch Lab, CIC bioGUNE-Basu o, Biobizkaia Heal h Resea ch Ins i u e, Ba acaldo, Spain. 4 Ike basque, Basque Founda ion o Science, Bilbao, Spain. 5 Biochemis y and Molecula Biology Depa men , Uni e si y o he Basque Coun y (UPV/EHU), Leioa, Spain. ✉email: [email p o ec ed]; aca[email p o ec ed] www.na u e.com/bjc B i ish Jou nal o Cance 1234567890();,: ha e been epo ed in glycolysis-p omo ing genes [10], de egu- la ed mRNA exp ession ep esen s a key con ibu ing ac o o ae obic glycolysis, which suppo ed he de elopmen o an- sc ip omic gene signa u es in di e en cance ypes [11–13]. And ogen ecep o plays a p edominan ole in con olling he exp ession o g ow h-p omo ing and an i-apop o ic genes in ol ed in a ious me abolic p ocesses, such as glycolysis [14]. Glucose anspo e s GLUT1 and GLUT2 a e egula ed a he ansc ip ional le el by he AR [15–17], whe eas con ol by AR- independen ac o s such as SOX2 and MYC p omo es p os a e cance p og ession, lineage plas ici y, and he apy esis ance [18,19]. In e es ingly, he Wa bu g e ec is obse ed bo h in localised PCa [20,21], as well as in ad anced disease o me as a ic lesions [22–24]. In his line, i has been epo ed ha he highes lac a e le els a e ound in pa ien s wi h PTEN loss, a gene ic ea u e o ad anced PCa [25]. The ac i a ion o he PI3K–AKT–mTOR signalling pa hway is belie ed o be a key ac o in PTEN-deficiency-d i en p os a e umo igenesis p omo ing ae obic glycolysis [26,27]. Inhibi ion o MCT4 (a plasma memb ane lac ic acid anspo e ), has been pos ula ed as a he apeu ic s a egy o educe glycolysis and lac ic acid sec e ion in neu oendoc ine p os a e cance (NEPC), a sub ype o agg essi e PCa [28]. In NEPC cell lines, inhibi ing MCT4 exp ession educed cell p oli e a ion in i o and glucose me abolism by down- egula ing glycoly ic genes. Howe e , da a abou he e ec i eness and oxici y o MCT4 inhibi ion in NEPC models in i o a e s ill lacking. Despi e he ele ance o glycolysis o umou cells, accumula - ing e idence sus ains ha bo h he ica boxylic acid (TCA) cycle and he OXPHOS pa hway a e s ill p esen and ac i e in he me as a ic se ing [6,29–36], which could complica e he use o lac a e- a ge ed he apies [27]. A p omising new small molecule, BKIDC-1553 (which exhibi s good sa e y and pha macologic p ope ies), has been shown o selec i ely inhibi he g ow h o PCa cell lines h ough i s an i-glycoly ic ac i i y. This is achie ed by inhibi ing hexokinase 2, as epo ed in a p eclinical xenog a model o ad anced PCa. The selec i e g ow h inhibi ion ac i i y o BKIDC-1553 is equi alen o ha o enzalu amide [37]. All hese esul s demons a e he complexi y and impac o me abolic in e ac ions wi hin umou s and in di e en s ages, highligh ing he impo ance o s udying d ug e ec s in di e se me abolic scena ios. T ica boxylic acid cycle (TCA) and oxida i e phospho yla ion (OXPHOS). The TCA comp ises a se ies o mi ochond ial chemical eac ions and is esponsible o p oducing ene gy and me abolic in e media es. I begins wi h he con e sion o ace yl-CoA (which is p oduced om he b eakdown o ca bohyd a es, a s, and p o eins) and oxaloace a e in o ci a e. Th ough a se ies o enzyma ic eac ions, ci a e is ans o med, esul ing in he p oduc ion o ca bon dioxide and molecules ca ying high- ene gy elec ons, namely NADH and FADH2. These elec on ca ie s a e subsequen ly u ilised o OXPHOS, a p ocess ha occu s in he inne mi ochond ial memb ane. OXPHOS in ol es he elec on anspo chain (ETC) and a p o on g adien , ul ima ely leading o he p oduc ion o ATP (Fig. 1). Despi e he ini ial pe cep ion o a gene al educ ion o he use o glucose de i a i es in he mi ochond ia, ecen e idence shows ha he e is umou - ype specifici y in his ep og amming. Whe eas panc eas, lung and colon umou s exhibi a slowe ATP p oduc ion han heal hy issues, b eas cance -de i ed me as ases epo edly show as e TCA cycle a e han o ho opic p ima y umou s [38]. In line wi h hese esul s, an inc ease in OXPHOS gene exp ession was de ec ed in melanoma b ain me as asis (MBM) by di ec me aboli e p ofiling and [U- 13 C]-glucose acing in i o [39], which is associa ed o inc eased sensi i i y o hese lesions o pha macological OXPHOS inhibi ion [39]. Howe e , la e clinical ials o analyse he he apeu ical po en ial o he same OXPHOS inhibi o in ad anced solid umou s and acu e myeloid leukaemia showed only modes a ge inhibi ion and limi ed an i umou ac i i y a ole a ed doses and led o discon inua ion o he ials due o neu o oxici y [40]. In e es ingly, umou cells exhibi changes in he TCA ha go beyond he egula ion o i s ac i i y. Mu a ions in he TCA cycle o he ETC machine y induce TCA cycle Glucose Heal hy p os a e luminal cell Ci a e Glucose Cy oplasm Py u a e Zinc Zinc Aconi ase Ci a e STOP ATP NADH Mi ochond ia Ci a e Lac a e Lac a e ATP TCA cycle Glucose P os a e cance Ci a e Glucose Cy oplasm Py u a e Zinc Aconi ase NADH Mi ochond ia Me as asis Lac a e Glucose Ci a e Glucose Cy oplasm Py u a e Aconi ase NADH Mi ochond ia Glucose 6P F uc ose 6P PPP G lycolysi s O XPH OS HBP G6PD Glycosida ion ATP Glucose 6P F uc ose 6P Glycosyla ion ATP 6GPD NADPH G6PD 6GPD G l y col y si s Gl y col y si s ATP Glucose 6P F uc ose 6P HBP H BP O XPH OS O XPH OS PPP PPP Glycosyla ion ? NADPH G6PD 6GPD abc TCA cycle ATP Lipids Lipogenesis Lipids Lipogenesis Zinc NADPH Fig. 1 Schema ic o e iew o he me abolic ewi ing occu ing in p os a e epi helial cells du ing he di e en s ages o cance p og ession. a Heal hy p os a e luminal cells accumula e high le els o zinc (due o he o e exp ession o i s anspo e ), leading o he inhibi ion o mi ochond ial aconi ase, he key enzyme esponsible o he ci a e-isoci a e con e sion in he TCA cycle. This inhibi ion esul s in he unca ion o he TCA cycle and ci a e accumula ion and sec e ion. As a esul , no mal p os a e epi helial cells a e cha ac e ized by an ine ficien OXPHOS. bIn p os a e cance cells, in acellula zinc le els a e significan ly educed (due o a dec eased exp ession o i s anspo e ); his leads o he eac i a ion o aconi ase, es o ing he ci a e-isoci a e con e sion, and consequen ly o he TCA cycle and OXPHOS me abolic pa hways. In addi ion, bo h he hexosamine biosyn hesis pa hway (HBP) esul ing in glycosyla ion and he pen ose phospha e pa hway (PPP) ha gene a es NADPH and nucleo ides a e up egula ed in PCa cells. cMe as a ic PCa cells exhibi he Wa bu g e ec wi h pe sis en TCA cycle/OXPHOS and PPP ac i i y. C ea ed wi h BioRende .com. M. Pujana-Vaque izo e al. 1251 B i ish Jou nal o Cance (2024) 131:1250 – 1262 al e na i e me abolic ou es, such as educ i e ca boxyla ion obse ed in a ious cance ypes [41–47]. Beyond he e ec o mu a ions al e ing he TCA cycle, specific cell s a e ansi ions a e accompanied by p o ound TCA ep og amming comp ising he ex ami ochond ial use o ci a e ha egene a es oxaloace- a e [48]. P os a e epi helial cells do no oxidise he p oduced ci a e like mos no mal cells due o unca ed TCA cycle [49–53]. Ins ead, luminal p os a e cells, bu no basal cells [54], accumula e high mi ochond ial zinc (Zn 2+ ). Zn 2+ inhibi s he mi ochond ial enzyme (m)-aconi ase, esponsible o ci a e oxida ion, and he accumu- la ed ci a e is subsequen ly sec e ed in o he p os a ic fluid. While basal cells p e e en ially gene a e ci a e h ough py u a e dehyd ogenase, luminal cells p edominan ly gene a e ci a e h ough py u a e ca boxylase ac i i y [54]. Me abolism o py u a e, aspa a e, glu amine and b anched-chain amino acids (BCAA) migh con ibu e o eplenishing me aboli es o he unca ed TCA cycle in PCa [55,56]. AR induces a me abolic ep og amming encompassing hZIP1 zinc anspo e down- egula ion ha leads o low mi ochond ial zinc le els [57,58] and m‐aconi ase eac i a ion, es o ing he TCA cycle [59], and inc easing he suscep ibili y o PCa cells o OXPHOS inhibi o s [60]. Oxida i e phospho yla ion can be a ge ed by es ic ing he supply o NADH o by di ec ly inhibi ing componen s o he ETC. Mu a ions in he mi ochond ial DNA encoding o OXPHOS machine y p omo e Wa bu g-like me abolism and an an i- umou immune esponse [61]. Ta ge ing he TCA cycle by comp omising mi ochond ial subs a e a ficking migh also be an e ec i e s a egy. Fo example, me o min and o enone, inhibi o s o complex-I (CI) o he ETC, inhibi p oli e a ion in se e al human cance cell lines, including PCa [62–64]. E idence has shown ha me o min has mul iple an ineoplas ic e ec s h ough AMPK-dependen and independen mechanisms, namely he al e a ion o IGF-1 signalling pa hways, supp ession o AR o mTOR pa hway, and lipogenesis. In line wi h his no ion, he e is e idence o educed mo ali y in PCa pa ien s ea ed wi h me o min [64]. The o enone de i a i e deguelin exhibi s an i umou al ac i i y in p eclinical mouse models o PCa based on he combined loss o P en and T p53 [65]. This e ec is associa ed o he al e na i e use o he ETC by P en-deficien cells, which consume ATP h ough mi ochond ial complex V ins ead o p oducing i . This obse a ion could be ansla ed o he use o CI inhibi o s in PCa pa ien s s a ified by PTEN s a us. Whe eas mos PCa esea ch is ocused on he e ec o AR signalling p omo ing TCA cycle [66,67], a deepe unde s anding o he AR-independen me abolic al e a ions is lacking and could be c i ical when designing he apeu ic s a egies in cas a ion- esis an pa ien s. Amino acid me abolism o he pen ose phospha e pa hway (PPP). The PPP is a main p oduce o NADPH and nucleic acid p ecu so s [68], which helps umou cells balance he edox s a us. Tumou cells exhibi de egula ion o oncogenes and umou supp esso genes ha con ol his pa hway [69]. Gene ic deficiency in glucose-6-phospha e dehyd ogenase (G6PD), one o he a e-limi ing enzymes o he PPP, is a common inhe i ed enzyme de ec and occu s almos exclusi ely in males [70–72]. The e is inc easing e idence ha his deficiency may o e p o ec ion agains s omach, colon, and li e cance . Con e sely, G6PD up egula ion has been associa ed wi h highe cance isk [73]. In as p oli e a ing cells, a high NADP + /NADPH a io ac i a es G6PD o suppo NADPH p oduc ion, leading o educ i e biosyn hesis o a y acids and nucleo ides. Fu he mo e, NADPH p omo es cell su i al unde oxida i e s ess condi ions such as mi ochond ial dys unc ion [74]. Up egula ed G6PD ac i i y is obse ed in a ious cance s, including papilla y hy oid ca cinoma, colo ec al, enal, hepa ocellula , b eas , and PCa [75–81]. Mechan- is ic esea ch in PCa cell lines sugges s ha AR-media ed egula ion o he PPP occu s h ough up egula ion o G6PD in esponse o mTOR complex 1 ac i a ion, leading o he p oduc ion o nucleo ide p ecu so s o DNA syn hesis and NADPH o p omo e lipogenesis [82] (Fig. 1). Indeed, PPP and G6PD ha e been p oposed as me abolic a ge s o PCa bone me as asis ea men [83]. In i o, gene ic and pha macological G6PD inhibi ion dec eased cance g ow h and mig a ion, leading o al e a ions in cellula edox balance and heigh ened sensi i i y o chemo he apy. In i o, G6PD gene ic abla ion esul ed in he educ ion o bone me as a ic bu den. A ecen s udy e ealed ha ano he PPP- ela ed enzyme, 6PGD, plays a key ole in PCa g ow h and su i al by coun e ac ing oxida i e s ess and unco e ed a no el eedback mechanism linking 6PGD and he AR signalling axis ha opens a new he apeu ical window o co- a ge ing AR and he PPP [84]. Gene ic o pha macological inhibi ion o 6PGD using physcion and S3 showed an icance ac i i y in agg essi e, cas a ion- esis an disease models as well as pa ien -de i ed umou explan s, pa ly due o inc eased oxida i e s ess. Ta ge ing o 6PGD was associa ed wi h wo impo an umou - supp essi e mechanisms: fi s ly, i inc eased he ac i i y o he AMP-ac i a ed p o ein kinase (AMPK); secondly, i enhanced AR ubiqui yla ion, leading o a educ ion in AR p o ein le els and ac i i y. Pha macological co- a ge ing o bo h ac o s was mo e e ec i e in supp essing he g ow h o PCa cells han single-agen he apies, indica ing posi i e eedback be ween AR and 6PGD. All hese findings sugges ha he PPP could be a aluable sou ce o a ge s o an icance d ug design and he apeu ic combina ion. Hexosamine biosyn he ic pa hway (HBP). The HBP is a me abolic ou e ha edi ec s 2–5% o glucose-de i ed ca bons away om glycolysis in non-cance cells. I comp ises he con e sion o he glycoly ic in e media e uc ose-6-phospha e o p oduce UDP-N- ace ylglucosamine (UDP-GlcNAc) [85]. UDP-GlcNAc se es as a subs a e o a ious cellula p ocesses, including p o ein glyco- syla ion—a c ucial pos - ansla ional modifica ion whe e suga s a e a ached o p o eins and lipids. Cance cells up egula e he flux owa ds he HBP and UDP-GlcNAc syn hesis by inc easing glucose and glu amine in ake o in esponse o oncogenic- associa ed signals like Ras [86], mammalian a ge o apamycin complex 2 (mTORC2) [87,88], and ans o ming g ow h ac o be a (TGF-β)[89]. In line wi h inc eased UDP-GlcNAc le els, b eas [90,91], lung [92], colon [92], li e [93], endome ial [94], ce ical [95], panc ea ic cance [96] and PCa [97] cells exhibi inc eased O-GlcNAcyla ion (Fig. 1). The e a e di e se molecula al e a ions ha con e ge on inc eased syn hesis o glycans. The second- a e limi ing enzyme o he HBP, UAP1 [98–100], is ele a ed in PCa, which p o ec s umou cells om ER s ess-induced cell dea h, hus pos ula ing i as a iable a ge o cance he apy. An enzyme in ol ed in he conjuga ions p ocess, he glycosyl ans- e ase GALNT7, is also up egula ed in PCa issues and p omo es p os a e umou g ow h [101]. Lessons om o he umou ypes e eal he me abolic c oss alk ha balances he use o glucose in e media y me aboli es. Loss o he PHGDH, an enzyme in ol ed in glucose-de i ed se ine biosyn hesis p omo es me as asis by ewi ing glucose owa ds HBP, hus inc easing in eg in glycosyla- ion [102]. Inc eased glycosyla ion influences he s uc u al di e si y in p o eins, including sialyla ion, ucosyla ion, O-β-N-ace ylglucosyla- ion, and he p esence o c yp ic and high-mannose N-glycans and p o eoglycan al e a ions [103]. Based on he e idence p esen ed, he apeu ic a ge ing o HBP ises as an inno a i e s a egy o selec i ely a ec cance cells, as non- ans o med cells would be mo e esilien o he pe u ba ion in O-GlcNAcyla ion [104,105]. Hexosamine analogues could se e his pu pose since hey exhibi an i umo al p ope ies. O he p omising he apeu ic s a egies in p eclinical models in ol e he pha macological inhibi ion o OGT, he HBP enzyme ha ca alyses he addi ion o he GlcNAc esidue o a ge p o eins. On he one hand, inhibi ing O-GlcNAcyla ion in PCa cells educed he exp ession o ma ix me allop o einase M. Pujana-Vaque izo e al. 1252 B i ish Jou nal o Cance (2024) 131:1250 – 1262 MMP-2, MMP-9, and VEGF, esul ing in inhibi ion o in asion and angiogenesis media ed by he egula ion o he oncogenic ansc ip ion ac o FoxM1 [104]. On he o he hand, OGT inhibi ion educed he p oli e a ion o PCa cells due o sus ained loss o c-MYC [97]. As a no e o cau ion, he equi emen o HBP o PCa cells migh be umo s age-dependen . In ac , cas a ion- esis an PCa shows dec eased HBP me aboli e and enzyme le els, sugges ing ha a ge ing he pa hway in his pa hological se ing could ha e unp edic able biological consequences [106]. O e all, unde s anding he unc ion and composi ion o glycop o eins and glycans ac oss all s ages o PCa will likely be c ucial o imp o ing disease managemen . The ele ance o he cell su ace glycan p ofile o cell-cell in e ac ions an icipa es ha HBP and glycosyla- ion ewi ing will ha e p o ound implica ions in he in e ac ions o umou cells wi h he TME. Lipid me abolism Lipid me abolic ep og amming encompasses al e a ions in a ious aspec s o lipid me abolism, including syn hesis, s o age, and ca abolism [107]. One significan adap a ion is he up egula- ion o lipogenic pa hways, whe e cance cells enhance he p oduc ion o a y acids and o he lipid componen s o sus ain hei apid g ow h. This inc ease in lipogenesis o en in ol es he ac i a ion o key enzymes such as ATP ci a e lyase (ACLY) and ace yl-CoA ca boxylase (ACC), d i en by oncogenic signalling pa hways like he PI3K/Ak /mTOR axis and MYC [108]. Addi ionally, cance cells exhibi changes in lipid up ake and u iliza ion, elying on bo h endogenous and exogenous lipid sou ces o sus ain hei me abolic needs. Dys egula ion o lipid me abolism is conside ed a hallma k in PCa [109]. These umou cells display dis inc al e a ions in lipid me abolism compa ed o no mal p os a e coun e pa s, and hese changes a e associa ed wi h umou g ow h, su i al, and me as asis [109]. Whe eas al e a ions in oncogenes and umou supp esso genes (p53 loss, PTEN loss, PI3K mu a ions) ha a e sha ed ac oss di e en umou ypes can al e his p ocess, enhanced lipid me abolism in PCa is p edominan ly d i en by AR signalling [110,111]. Indeed, AR con ols he ansc ip ion o enzymes in ol ed in a y acid syn hesis and oxida ion o ulfil he bioene ge ic and anabolic demands o PCa cells, and i also egula es lipid up ake and s o age, choles e ol, and phospholipid me abolisms [112] (Fig. 2). De no o lipogenesis (DNL). PCa is cha ac e ised by augmen ed DNL in bo h in ea ly and la e s ages o he disease [113]. This pa hway is igh ly egula ed and p oduces a y acids om non- lipidic p ecu so s. The p ima y subs a e in a y acid syn hesis is ace yl-CoA, which is ca boxyla ed by ace yl-CoA ca boxylase o o m malonyl-CoA [114]. Malonyl-CoA uni s a e hen sequen ially added o he g owing a y acid chain by a y acid syn hase Kidney Bladde P os a e AR SREBP Ci a e Ace yl - CoA Malonyl - CoA Palmi a e SFA MUFA Ace oace yl - CoA HMG - CoA Me alona e Choles e ol SREBP a ge genes de no o lipogenesis Choles e ol biosyn hesis ACAT ACAC ACLY FASN Lipid d ople s s o age Exogenous lipid up ake LDL LDLRFATPs CD36 ELOVL SCD FADS ELOVL HMGCS HMGCR Acyl-CoA CPT1 FABP5 Fa y acid Fa os a in C75 Du as e ide Fa y acid oxida ion Co egula o s AR a ge genes AR AR AR AR AR AR Hsp Hsp 5α- educ ase DHT Tes os e one AR media ed lipid me abolism in PCa Tumo al cell Al e ed lipid me abolism in he TME? S a ins Neu ophil Mac ophage Dend i ic cell T-Cell Endo helial cell Fa y acid Fa y acid Fa y acid Nucleus Mi ochond ia Cy oplasm SBFI-103 ATGL MAGL Lipolysis SQLE FR194738 Te bina ine Fig. 2 The landscape o lipid me abolism in PCa. The figu e illus a es he key aspec s o lipid me abolism in PCa, mainly d i en by AR-media ed cellula ep og amming o umo al cells. In esponse o AR signalling, PCa cells exhibi an augmen ed de no o lipogenesis h ough ansc ip ional egula ion by SREBPs. Mi ochond ial a y acid oxida ion, ia up egula ion o he CPT1 anspo e , gene a es ene gy o p oli e a ion. In addi ion, PCa cells inc ease exogenous a y acid up ake h ough up egula ed CD36 and FATPs. FABPs play a ole in he in acellula compa men aliza ion o a y acids. Dys egula ion o choles e ol me abolism also ep esen s a cha ac e is ic ea u e o p os a e umou s. The main enzymes and egula o s aking pa in hese pa hways a e highligh ed, alongside a ious inhibi o s s udied o po en ial he apeu ic in e en ions. Finally, he s udy o lipid me abolism in cells comp ising he TME eme ges as an impo an s a egy o u u e esea ch. Abb e ia ions: AR; and ogen ecep o , DHT; dihyd o es os e one. C ea ed wi h BioRende .com. M. Pujana-Vaque izo e al. 1253 B i ish Jou nal o Cance (2024) 131:1250 – 1262 (FASN). This p ocess con inues h ough a se ies o chemical eac ions un il a long-chain a y acid is syn hesised. The esul ing a y acids can be u he modified, inco po a ed in o phospho- lipids o memb ane biogenesis, o s o ed as iglyce ides [115]. S e ol- egula o y elemen -binding p o eins (SREBPs) a e an- sc ip ion ac o s ha play a c ucial ole in egula ing lipid syn hesis. SREBP-1 is up egula ed along PCa p og ession [111,112], pa ly in an AR-dependen manne [116,117], and i ac i a es he exp ession o enzymes in ol ed in de no o lipogenesis, including FASN [118,119]. Di e en s a egies ha e been de eloped o a ge DNL in PCa. P eclinical s udies using SREBP inhibi o s such as a os a in suppo he idea ha a ge ing his pa hway is an in e es ing s a egy o block PCa g ow h and p omo e apop osis [120]. Fa os a in inhibi s SREBP clea age-ac i a ing p o ein (SCAP), a key egula o o lipid me abolism. SCAP is esponsible o anspo ing he SREBPs om he endoplasmic e iculum (ER) o he Golgi appa a us, whe e hey unde go p o eoly ic clea age o ac i a e he ansc ip ion o genes in ol ed in choles e ol and a y acid syn hesis. By inhibi ing SCAP, a os a in p e en s he ansloca ion o SREBPs o he Golgi, hus inhibi ing hei ac i a ion and subsequen ansc ip ional egula ion o lipid syn hesis [120]. In addi ion, du as e ide and C75 a e wo FASN inhibi o s ha ha e been de eloped and es ed o hei e ec i eness in PCa [121–123]. Du as e ide indi ec ly educes FASN mRNA le els by inhibi ing he enzyme 5α- educ ase, which is esponsible o con e ing es os e one in o dihyd o es os e one [121]. C75 inhibi s FASN h ough compe i i e binding, hus p e en ing he syn hesis o a y acids om ace yl-CoA and malonyl-CoA [122]. Despi e a ious e o s o a ge lipid syn hesis, a c i ical challenge pe sis s in elucida ing p ecise bioma ke s and me hodol- ogies o he iden ifica ion o lipogenic umou s and he s a ifica- ion o pa ien s likely o exhibi op imal esponses o DNL a ge ing. Fo ha eason, new a ge s o he DNL pa hway a e cu en ly being explo ed o he apeu ic pu poses. Recen ly, a la ge-scale analysis e ealed ha he a y acid elongase ELOVL5 is up egula ed in PCa and i s deple ion leads o an i umo al esponses [124]. Concomi an ly, he ELOVL5 enzyme also gene a es polyunsa u a ed a y acids (PUFAs), which ha e been associa ed wi h enzalu amide esis ance du ing neu oendoc ine di e en ia ion (NED) by ac i a - ing he AKT-mTOR pa hway [125]. Lipolysis and a y acid oxida ion (FAO). Lipolysis e e s o he p ocess ha con e s s o ed a s o iglyce ides in o glyce ol and a y acids. In he con ex o PCa, lipolysis is up egula ed o gene a e a y acids ha a e subsequen ly used as an ene gy sou ce and building blocks o cellula componen s [126]. Howe e , lipolysis is a mo e complex p ocess han lipid syn hesis. I equi es a balance be ween a y acid ca abolism, necessa y o biomass, and he need o ATP and NADPH p oduc ion. Ele a ed le els o monoacylglyce ol lipase (MAGL) in AR-independen p os a e cance con ibu e o malignancy h ough endocannabi- noid and a y acid pa hways [127]. Complemen a ily, adipose iglyce ide lipase (ATGL) exp ession co ela es wi h wo se p ognosis in CRPC pa ien s [128]. Inhibi ion o ATGL impai s PCa cell g ow h in i o and in i o, inducing a me abolic shi owa ds glycolysis [128]. A e being eleased om s o age uni s, lipids can be ca abolised h ough a y acid oxida ion (FAO), a p ocess whe e cells u ilise FAO as an ene gy sou ce, and ha is al e ed in PCa [129]. CPT1, he enzyme ha anspo s medium-long a y acids in o he mi ochond ia o oxida ion, is up egula ed in PCa [130,131]. In addi ion, FAO could sus ain a cas a ion- esis an s a e, which has been demons a ed ecen ly h ough he inhibi ion o 2,4-dienoyl-CoA educ ase (DECR1) [132,133]. Fa y acid up ake and anspo . Fa y acid anspo p o eins (FATPs) and a y acid binding p o eins (FABPs) a e esponsible o he up ake o exogenous and in acellula anspo o a y acids, espec i ely. These p o eins a e up egula ed in PCa, which heo e ically inc eases a y acid a ailabili y o cellula p ocesses [134,135]. FABP5 inhibi ion p o ides a syne gis ic e ec in combina ion wi h chemo he apy [136], and he epo ed depen- dence o PTEN loss-d i en PCa [137] on his enzyme encou ages he e alua ion o his he apeu ic s a egy in a s a ified popula ion. Indeed, SBFI-103, a compe i i e inhibi o o FABP5, is e ec i e and well- ole a ed bo h in i o and in i o in PCa cells esis an o ADT o axanes [137]. Finally, CD36, a mul i unc ional cell su ace ecep o ha impo s a y acids, con ibu es o a ious aspec s o PCa biology, including umou g ow h, angiogenesis, and me as asis. The umou supp essi e conse- quences o Cd36 dele ion in P en loss-induced PCa [138] sugges ha knowledge and he apeu ic s a egies epo ed o o he umou ypes could be implemen ed in his disease [139,140]. FA6.152, an an i-CD36 neu alising an ibody, inhibi s all known unc ions o CD36, including i s in e ac ions wi h h ombospondin, collagens, and a y acids. Simila ly, ano he CD36 a ge ing an ibody named JC63.1 selec i ely blocks up ake o a y acid and oxidised low-densi y lipop o eins. T ea men o o al squa- mous cell ca cinoma (OSCC) models wi h hese wo an ibodies impai me as asis [139]. Choles e ol me abolism. PCa cells o en exhibi inc eased de no o choles e ol biosyn hesis [141–143], and AR signalling con ols he exp ession o choles e ol biosyn he ic enzymes, such as HMG-CoA educ ase (HMGCR) [144]. The ele ance o his pa hway in PCa spans mul iple biological aspec s. Fi s , choles e ol is a c i ical p ecu so o he syn hesis o s e oid ho mones, including and ogens, which sus ains he ac i a ion o AR in umou cells a e cas a ion he apy [145–147]. Second, choles e ol is a c i ical componen o lipid a s, memb ane mic odomains ha play a ole in cellula signalling. Al e a ions in choles e ol le els a ec lipid a dynamics and he associa ed signalling pa hways in ol ed in PCa p og ession [141]. Thi d, choles e ol es e s a e abundan componen s o lipid d ople s, whose p esence is associa ed wi h PCa agg essi eness [148]. Gi en he ele ance o choles e ol me abolism in cance , di e en he apeu ic s a egies ha e been p oposed o PCa. S a ins a e choles e ol-lowe ing agen s ha a e adminis e ed ch onically o millions o people a ound he globe. Since hey inhibi HMGCR, hei po en ial an icance ac i i y has been b oadly s udied [149]. In his ega d, high doses o s a ins in i o consis en ly educe PCa agg essi eness [150,151]. Howe e , low doses o some o hese d ugs (equi alen o he concen a ions eached in he blood o ea ed indi iduals) exhibi pa adoxical e ec s on umou cells in i o and in i o [152]. This disc epancy is e iden in epidemiological s udies moni o ing he influence o s a in ea men in PCa pa hogenesis and p og ession [149], sugges ing ha we s ill miss c i ical biological in o ma ion ega ding how hese d ugs ope a e in cance . Choles e ol me abolism could be pa icula ly ele an when a ge ing and ogen p oduc ion o signalling in PCa. Indeed, inhibi ion o squalene epoxidase (SQLE), a c ucial enzyme in choles e ol biosyn hesis, has been p oposed as a p omising pha macological in e en ion o ea ing CRPC [153,154]. Ta ge - ing SQLE wi h e binafine e ec i ely inhibi ed o ho opic umou s g ow h in mice. Mo eo e , in a clinical se ing, e binafine demons a ed he abili y o dec ease p os a e-specific an igen (PSA) le els in h ee ou o ou la e-s age p os a e cance pa ien s [154]. Simila ly, he pha macologic blockade o SQLE wi h FR194738 a enua ed he g ow h o PC3 cells bo h in i o and in mouse xenog a models [153]. Finally, a complemen a y s a egy o suppo and ogen syn hesis in condi ions o ho mone dep i a ion is he p o ision o choles e ol by he TME. In his line, mac ophages can se e as a sou ce o choles e ol o PCa cells in he con ex o and ogen dep i a ion, hence suppo ing he de elopmen o CRPC [155]. M. Pujana-Vaque izo e al. 1254 B i ish Jou nal o Cance (2024) 131:1250 – 1262 One-ca bon me abolism One-ca bon (1 C) me abolism in ol es wo cen al cycles: he ola e cycle and he me hionine cycle [156]. In he ola e cycle, e ahyd o ola e (THF) ac s as a ca bon ca ie o pu ine and hymidyla e syn hesis. Me hyl g oups ans e om 5-me hyl THF o homocys eine, o ming me hionine and connec ing he wo cycles. Me hionine is con e ed o S-adenosyl-me hionine (SAM), a uni e sal me hyl dono o p o ein and DNA me hyla ion. SAM is hen me abolized o S-adenosyl-homocys eine (SAH) and la e o homocys eine, comple ing he cycle. Homocys eine p oduces cys a hionine in he anssul u a ion pa hway, a p ecu so o glu a hione. SAM can also eed in o he polyamine biosyn hesis pa hway h ough i s deca boxyla ion by S-adenosylme hionine deca boxylase (AMD1) [157] (Fig. 3). Al e a ions in 1 C me abolic homeos asis a e a he co e o di e en diseases including cance [156]. Tumou cells depend on 1 C me abolism o DNA syn hesis, edox balance, me hyla ion eac ions and polyamine biosyn hesis. All hese p ocesses a e ele an ac oss di e en cance s and con ibu e o umou p og ession [158,159]. In PCa, and ogen signalling egula es he ac i i y o 1 C enzymes in ol ed in SAM homeos asis, he anssul u a ion pa hway and polyamine biosyn hesis [160]. In u n, changes in AR ac i i y occu ing upon PCa p og ession and he apy can influence 1 C me abolism and he in ica e epigene ic c oss alk [160]. SAM homeos asis. GNMT and mi ochond ial SARDH a e c i ical enzymes ha con ol SAM a ailabili y. They a e egula ed by and ogen signalling and a e equen ly al e ed in PCa [161,162]. GNMT ans e s a me hyl g oup om SAM o glycine o o m SAH and sa cosine, whe eas SARDH deme hyla es sa cosine o o m glycine [163]. These wo eac ions de e mine he SAM:SAH a io o he main enance o epigene ic esponses, and he p oduc ion o sa cosine in his me abolic s ep has been p oposed as a bioma ke in PCa, al hough his da a gene a ed in ensi e con o e sy in he field [164,165]. GNMT, is epo ed o be bo h up egula ed and down egula ed depending on he s udy, hus sugges ing a mul i ac o ial egula ion in he di e en s ages o he disease [166,167]. A easible explana ion ela es o egula ing GNMT by signalling pa hways ha exhibi ecip ocal nega i e eedback egula ion [168,169]. AR has a p edominan ole in sus aining GNMT exp ession, whe eas PI3K ac i a ion induces i s ep ession [170], a p ocess ha could depend on FOXO egula ion, acco ding o s udies in D osophila melanogas e [171]. In e es - ingly, Gnm le els a e p o oundly educed in P en loss-d i en mu ine PCa, bu a ge mline dele ion o he me abolic enzyme educed PCa incidence in his model, hus sugges ing ha ei he esidual GNMT ac i i y is essen ial o umo igenesis o ha his enzyme plays a c i ical ole in he TME [170]. Finally, a ecen s udy has shown a mTORC1/ATF4-d i en down egula ion o p o ein kinase C (PKC) λ/ι in neu oendoc ine p os a e cance ha inc eases se ine biosyn hesis. This me abolic shi suppo s cell p oli e a ion and ele a es in acellula SAM le els, p omo ing epigene ic changes cha ac e is ic o his agg essi e o m o PCa [172]. The anssul u a ion pa hway. The anssul u a ion pa hway is a b anch o 1 C me abolism ha con e s homocys eine o cys eine. This p ocess in ol es se e al enzyma ic s eps, wi h cys a hionine be a-syn hase (CBS) playing a p edominan ole [173]. CBS ac i i y is con olled by SAM pools o di ec homocys eine owa ds eme hyla ion when SAM le els a e low [173]. In PCa, s udies showing bo h inc eased and dec eased exp ession o CBS ha e been published [174,175]. Lowe enzyme le els a e ound in me as a ic PCa cell lines, bu hese da a do no co ela e wi h Cy oplasm Nucleus 3-PG Se ine Glycine 5,10-me hylene-THF THF 5-me hyl-THF 5- o myl-THF Me hionine DMG Be aine Homocys eine SAM SAH CH3 Cys a hionine Cys eine GSH Die GLDC MTHFR MTR Folic acid DHFR BHMT MAT SAHH HMT CBS CTH SSP SHMT Glycine Sa cosine Sa cosine Glycine GNMT SARDH dc-SAM AMD1 A ginine O ni hine Spe mine Pu escine Spe midine A ginase ODC1 SRM SMS MTA MTA F ola e c y cle Me hionine c y cle T anssul u a ion pa hw a y P ol y amines pa hw a y * * ** * * * * * ** *AR esponsi e genes Fig. 3 1 C me abolism in PCa. Main me aboli es and enzymes in ol ed in 1 C me abolism. This pa hway encompasses he ola e and me hionine cycles, essen ial o cellula p ocesses like DNA syn hesis and me hyla ion. Addi ionally, i links o he anssul u a ion pa hway, main aining edox powe h ough glu a hione syn hesis, and influencing ansla ion and p oli e a ion ia he polyamine biosyn hesis pa hway. Red as e isks indica e AR- esponsi e enzymes desc ibed in he li e a u e. Abb e ia ions: 3-PG 3-phosphoglyce a e, THF e ahyd o ola e, DMG dime hylglycine, SAM S-Adenosylme hionine, dc-SAM deca boxyla ed S-Adenosylme hionine, SAH S-adenosylhomo- cys eine, MTA 5’-me hyl hioadenosine, GSH glu a hione. C ea ed wi h BioRende .com. M. Pujana-Vaque izo e al. 1255 B i ish Jou nal o Cance (2024) 131:1250 – 1262 clinical e idence epo ing inc eased homocys eine and cys a hio- nine abundance in pa ien s wi h wo se ou comes [176,177]. In his line, cys ine deple ion sensi ises PCa cells o immune checkpoin inhibi o s as well as o DNA damage-inducing agen s, u he highligh ing he impo ance o hese in e media es in PCa [178]. Polyamine biosyn hesis. Polyamines (PA) a e small polyca ions essen ial o no mal cell g ow h in all euka yo ic o ganisms [179]. Pu escine is gene a ed om he u ea cycle h ough deca boxyla- ion o o ni hine by o ni hine deca boxylase (ODC1), whe eas AMD1 deca boxyla es SAM o dcSAM. This eac ion p o ides he p opyl amines necessa y o o m spe midine and spe mine om pu escine h ough he ac ion o spe midine syn hase (SRM) and spe mine syn hase (SMS) [180]. The p os a e epi helium syn he- sises high le els o polyamines ha a e sec e ed in o he seminal fluid. And ogens con ol his p ocess h ough ansc ip ional egula ion o ODC1 and AMD1 [181,182]. Acco dingly, and ogen dep i a ion he apies educe he abundance o spe midine and spe mine [183]. Howe e , egula ion o PA biosyn hesis in PCa ex ends beyond AR signalling. On he one hand, ODC1 is a main a ge o MYC, which associa es MYC amplifica ion and o e - exp ession wi h ele a ed polyamine biosyn hesis [184]. The egula ion o polyamine biosyn hesis downs eam MYC con i- bu es o he umou supp essi e ac i i y o PGC1α, which was ecen ly epo ed o ep ess his oncogene [185–187]. On he o he hand, PI3K-mTORC1-dependen egula ion o AMD1 s abili y influences polyamine syn hesis [188], an obse a ion ha is ex ensible o o he pa hophysiological con ex s beyond cance [189]. TUMOR CELL-EXTRINSIC METABOLIC INFLUENCES P os a e cance is associa ed wi h ageing, and in u n, he o ganism and cellula en i onmen ep esen an impo an modifiable ac o in he pa hogenesis and p og ession o he disease. The e is an eme ging in e es in s udying he me abolic p ope ies o he umou mic oen i onmen , as well as how exogenous ac o s like he die may impac umou p og ession. The TME closely in e ac s wi h umou cells and comp ises immune cells, fib oblas s, blood essels, and he ex acellula ma ix [190]. Immune cells wi hin he TME can ei he igge p o- umo al o an i- umo al esponses [191], while he ex acellula ma ix and s omal cells wi hin he TME p o ide s uc u al and biochemical suppo o umou s, influencing hei abili y o in ade su ounding issues and me as asize [190]. Ad ances in high- h oughpu , single-cell esolu ion echnologies ha e significan ly enhanced ou comp ehension o cellula di e si y in PCa [192–194]. Howe e , he e is s ill e y li le knowledge abou he me abolic adap a ions in PCa s omal cells, and a glimpse a o he umou ypes can p o ide c i ical in o ma ion on wha is o come (Fig. 4). Glucose me abolism in he TME The ele a ed glycoly ic a e o umou cells is di ec ly esponsible o c ea ing he acidic and nu ien -deple ed condi ions o he TME, which ha e p o ound consequences o immune ac i i y [195,196]. One o he mos significan e ec s o ae obic glycolysis is he acidifica ion o he TME due o lac a e sec e ion [197,198], which suppo s inc eased mig a ion and in asion [199] and p omo es immune ep og amming owa ds a ole an pheno ype [196,200]. Glycolysis in he umou s oma is also equi ed o adequa e an i umo al esponse, which has led o he de elop- men o me aboli e-based o mula ions in he p esence o a glycoly ic inhibi o ha specifically a ge s cance cells [201]. Cance and T cells compe e o glucose among se e al o he me aboli es, and he a idi y o cance cells o his nu ien diminishes he cy oly ic ac i i y [195,202,203]. Glycoly ic capaci y in T cells is also influenced by oncome aboli es such as 2-hyd oxyglu a a e, which is p oduced a high concen a ions in isoci a e dehyd ogenase mu an cance s and inhibi s hei p oli e a ion, cy okine p oduc ion, and abili y o kill umou cells [204]. Lipid me abolism in he TME Lipid me abolism is simila ly equi ed in s omal cells. SREBP ac i i y o ches a es he immune esponses in cance . Inhibi ion o SREBP unc ion in egula o y T cells (T eg) enhances an i umou immune esponses [205]. Pa icula ly, SREBP-clea age-ac i a ing p o ein dele ion in in a- umo al T egs inhibi s umou g ow h and imp o es PD-1- igge ed immuno he apy by egula ing in e e on-γp oduc ion [205]. Simila ly, dele ion o FABP5 in T eg a ec s mi ochond ial in eg i y and igge s cGAS-STING- dependen ype I IFN signalling [206]. Mac ophages a e egula ed by umou cells a mul iple le els and hei pola isa ion con ibu es o he acquisi ion o agg essi e ea u es. Up egula ion o CD36 in me as asis-associa ed mac ophages (MAMs) p omo es umou cell-de i ed a y acid up ake, p o umou al pola iza ion and hei suppo i e ole in he es ablishmen o li e me as asis [207]. Thus, a ge ing CD36 eme ges as a wo-hi s a egy a ge ing bo h umou and immune cells in he ea men o me as asis. Lipids can also suppo he ac i a ion o lymphocy es. As an illus a i e example, linoleic acid ac i a es CD8 +T cells, enhancing me abolic fi ness and p e en ing exhaus ion [208], highligh ing i s ole as a po en ial adju an o po en ia e adop i e T cell he apy. One-ca bon me abolism in he TME Ve y li le is known abou he con ibu ion o 1 C me abolism o he TME in PCa. In u n, sca e ed e idence in o he umou ypes can p o ide an idea o he p ocesses influenced by his me abolic ou e in cance . Deficiencies in one-ca bon me abolism impai he e ec i eness o PD-1 blockade in melanoma. Cohe en ly, aug- men ing 1 C me abolism h ough o ma e supplemen a ion du ing an i-PD-1 he apy imp o es CD8 +T-cell fi ness and acili a es CD8 +T-cell-media ed umou clea ance [209]. These esul s indica e ha o ma e supplemen a ion has he po en ial o enhance he unc ion o exhaus ed CD8 +T cells. Impo an ly, he acidifica ion o he ex acellula milieu also influences T cell unc ion, elici ing a educ ion in me hionine me abolism ia SLC7A5 down egula ion ha esul s in a ‘s em-like memo y’s a e. This ep og amming enhances T cell pe sis ence and an i- umou e ficacy in mice, e ealing a no el influence o acidic condi ions on T cell cha ac e is ics [210]. The ele ance o 1 C me abolism o glu a hione p oduc ion and edox balance is an addi ional ac o con olling he ac i i y o he TME. Dis up ing glu a hione syn hesis in T egs impai s hei abili y o egula e se ine me abolism, leading o se e e au oimmuni y and imp o ed an i- umou esponses [211]. Tumou -in insic 1 C me abolism p o- duces sec e ed me abolic in e media es ha can emodel he TME. Tumou cells exhibi equen loss o me hyl hioadenosine phospho ylase (MTAP), which leads o he accumula ion o i s subs a e MTA [212]. Sec e ed MTA is up aken and me abolized by fib oblas s, which will p oduce and sec e e bo h pu ine p oduc s and cy okines ha induce mac ophage pola iza ion. Die and obesi y Nu i ion ep esen s he igh es in e ac ion o ou o ganism wi h he en i onmen . As such, i is closely linked o he de elopmen o diseases, including cance . S udies in o he umou ypes ha e un eiled addi ional molecula p ocesses esponsible o he high- a die -induced pheno ype. In o al ca cinoma and melanoma models die a y palmi ic acid, bu no oleic o linoleic acid, p omo es me as asis in mice [139,140]. Molecula ly, palmi ic acid induces a p o-me as a ic memo y in ol ing CD36, his one modifica ions, and a neu al signa u e linked o Schwann cells, M. Pujana-Vaque izo e al. 1256 B i ish Jou nal o Cance (2024) 131:1250 – 1262 leading o bo h me as asis ini ia ion and long- e m me as a ic memo y. These same modifica ions may also play a ole in PCa [140]. In line wi h he ole o CD36, a high- a die has been shown o p omo e me as asis by enhancing sa u a ed a y acid up ake ia his ecep o in b eas cance [213]. Modifica ions in die a y habi s could also be beneficial o cance pa ien s. Calo ic es ic ion induces an i-p oli e a i e e ec s in mouse xenog a s, an e ec ha is limi ed o umou s wi hou mu a ions causing cons i u i e ac i a ion o he PI3K pa hway [214]. Mo e ecen ly, calo ic es ic ion has been shown o inhibi he g ow h o ce ain umou s in mice by lowe ing lipid le els in bo h plasma and umou s [215]. This die a y modifica ion educes s ea oyl-CoA desa u ase ac i i y in cance cells, causing an imbalance be ween unsa u a ed and sa u a ed a y acids and impai ing umou g ow h. In PCa obesi y has been linked o an inc eased isk and p og ession o he disease in epidemiological s udies [216–218], owing o he con ibu ion o ac o s such as insulin esis ance, ch onic inflamma ion, o ho monal dys egula ion, among o he s. Howe e , he causal con ibu ion o obesi y o PCa and he mechanis ic ounda ions o his e ec emains elusi e. Mu ine models ha e shed some ligh on hese ques ions. Obesi y and high calo ie-induced hype insulinemia p omo e PCa in p os a e- specificP en -/- mice by inc easing cell p oli e a ion and ac i a ing insulin/IGF1/PI3K/AKT signalling pa hways [219,220]. In line wi h his no ion, mu a ions in PCa ha ac i a e PI3K (such as p os a e- specificP en loss) p ime o p omo e obesi y-d i en PCa agg es- si eness in conjunc ion wi h o he signalling pa hways, such as loss o P pn1 [221], IL6/pSTAT3 signalling ac i a ion [222]o Pml co-dele ion [223]. This knowledge o e s new he apeu ic oppo - uni ies o a ge ing PTP1B, IL6 o PML-loss induced SREBP signalling in he con ex o obesi y. Al hough much o he emphasis on he influence o obesi y has been pu on lipid a ailabili y and ch onic inflamma ion, suga s could also play a ele an ole. Indeed, inc eased exp ession o uc ose anspo e s in PCa has been sugges ed o p omo e uc ose up ake and me abolism o suppo cance cell fi ness [224]. Collec i ely, die a y in e en ions may also play a ole in bo h he p og ession and ea men o PCa, and u he s udies a e equi ed o ex end he knowledge o molecula and biological e ec o s ha can be ansla ed in o p e en i e and he apeu ic ac ions. Tumo al cell Immune ole ance Lac a e Lac a e In asion Neu ophil Mac ophage Dend i ic cell T-Cell SCAP o FABP5 dele ion T-Cell Enhanced immuno he apy e ec i i y Mac ophage CD36 up egula ion Me as asis + immunosup ession FA Enhanced immune e ec i i y T-Cell Linoleic acid GSH inhibi ion Fo ma e IDH mu an s 2-HG T-Cell Reduced immune e ec i i y Fib oblas MTAP dele ion MTA Pu ines + Cy okines Mac ophage pola iza ion Die in e en ions Obesi y P en/PTP1B/IL6/PML dele ion Palmi ic acid Me as asis F uc ose in ake Calo ic es ic ion P oli e a ion Tumo al Cell Na u al kille cell Fig. 4 The ole o me abolism in he cance umou mic oen i onmen . Summa y o he ecen concep s ega ding he in e ac ion o umou me abolism wi h he umou mic oen i onmen o suppo cance p og ession. Abb e ia ions: 2-HG 2-Hyd oxyglu a a e, GSH glu a hione, IDH isoci a e dehyd ogenase, MTAP S-me hyl-5’- hioadenosine phospho ylase, MTA 5′-deoxy-5′-me hyl hioadenosine. C ea ed wi h BioRende .com. M. Pujana-Vaque izo e al. 1257 B i ish Jou nal o Cance (2024) 131:1250 – 1262 CONCLUDING REMARKS AND OPEN QUESTIONS O e he pas decade, he e ha e been ex ensi e e o s o unde s and he mechanisms and biological consequences o me abolic ep og amming in cance . Al hough cu en ly he e a e no d ugs app o ed o PCa ea men ha a ge specific me abolic pa hways, he e a e mul iple agen s in de elopmen . Me abolic ep og amming is essen ial o he biology o cance cells. Tumou me abolism is influenced by cance cell-specific me abolic adap a ions as well as by me abolic al e a ions in he TME. Mode n echnologies o s udy me abolism, including new imaging echniques, spa ial me abolomics and single-cell RNA sequencing ha e edefined ou knowledge o cance me abolism. Howe e , despi e ex ensi e esea ch in PCa me abolism, he e is s ill a gap in knowledge on he he apeu ically-ac ionable me abolic pa hways ha a e ele an o each s age o he disease. Fu he esea ch in o he me abolic dependencies o he p ima y umou and hose o he me as a ic lesions, including he ole o e op osis, hypoxia and mic obio a, migh lead o new me abolic in e en ions o p e en me as a ic dissemina ion o p os a e cance , and o significan imp o emen s in he cu a ion a e o his disease. REFERENCES 1. Heinlein CA, Chang C. And ogen ecep o in p os a e cance . Endoc Re . 2004;25:276–308. 2. Gibson DA, Saunde s PTK, McEwan IJ. And ogens and and ogen ecep o : abo e and beyond. Mol Cell Endoc inol. 2018;465:1–3. 3. Dehm SM, Tindall DJ. Molecula egula ion o and ogen ac ion in p os a e cance . J Cell Biochem. 2006;99:333–44. 4. Ba eld SJ, I konen HM, U banucci A, Mills IG. And ogen- egula ed me abolism and biosyn hesis in p os a e cance . Endoc Rela Cance . 2014;21:T57–66. 5. Wa bu g O, Wind F, Negelein E. The me abolism o umo s in he body. J Gen Physiol. 1927;8:519–30. 6. DeBe a dinis RJ, Chandel NS. We need o alk abou he Wa bu g e ec . Na Me ab. 2020;2:127–9. 7. Luengo A, Li Z, Gui DY, Sulli an LB, Zago ulya M, Do BT, e al. Inc eased demand o NAD(+) ela i e o ATP d i es ae obic glycolysis. Mol Cell. 2021;81:691–707.e6. 8. Wang Y, S ancli e E, Fowle-G ide R, Wang R, Wang C, Schwaige -Habe M, e al. Sa u a ion o he mi ochond ial NADH shu les d i es ae obic glycolysis in p oli e a ing cells. Mol Cell. 2022;82:3270–83.e9. 9. Vaa we k B, B eunis WB, Ha eman LM, de Keize B, Jehanno N, Bo gwa d L, e al. Fluo ine-18-fluo odeoxyglucose (FDG) posi on emission omog aphy (PET) compu ed omog aphy (CT) o he de ec ion o bone, lung, and lymph node me as ases in habdomyosa coma. Coch ane Da abase Sys Re . 2021;11:CD012325. 10. G aham NA, Minasyan A, Lomo a A, Cass A, Balanis NG, F iedman M, e al. Recu en pa e ns o DNA copy numbe al e a ions in umo s eflec me abolic selec ion p essu es. Mol Sys Biol. 2017;13:914. 11. Wei J, Huang K, Chen Z, Hu M, Bai Y, Lin S, e al. Cha ac e iza ion o glycolysis- associa ed molecules in he umo mic oen i onmen e ealed by pan-cance issues and lung cance single cell da a. Cance s (Basel). 2020;12:1788. 12. Mi chell KG, Amini B, Wang Y, Ca e BW, Godoy MCB, Pa a ER, e al. 18)F- fluo odeoxyglucose posi on emission omog aphy co ela es wi h umo immunome abolic pheno ypes in esec ed lung cance . Cance Immunol Immuno he . 2020;69:1519–34. 13. Ma hews EH, Liebenbe g L, Pelze R. High-glycoly ic cance s and hei in e play wi h he body’s glucose demand and supply cycle. Med Hypo heses. 2011;76:157–65. 14. Uo T, Sp enge CC, Plyma e SR. And ogen ecep o signaling and me abolic and cellula plas ici y du ing p og ession o cas a ion esis an p os a e cance . F on Oncol. 2020;10:580617. 15. Whi e MA, Tsouko E, Lin C, Rajapakshe K, Spence JM, Wilken eld SR, e al. GLUT12 p omo es p os a e cance cell g ow h and is egula ed by and ogens and CaMKK2 signaling. Endoc Rela Cance . 2018;25:453–69. 16. Xu M, Sakamo o S, Ma sushima J, Kimu a T, Ueda T, Mizokami A, e al. Up- egula ion o LAT1 du ing an iand ogen he apy con ibu es o p og ession in p os a e cance cells. J U ol. 2016;195:1588–97. 17. Wang J, Xu W, Wang B, Lin G, Wei Y, Abudu exi i M, e al. GLUT1 is an AR a ge con ibu ing o umo g ow h and glycolysis in cas a ion- esis an and enzalu amide- esis an p os a e cance s. Cance Le . 2020;485:45–55. 18. de We L, Williams A, Gilla d M, K egel S, Lampe is S, Gu gesell LC, e al. SOX2 media es me abolic ep og amming o p os a e cance cells. Oncogene. 2022;41:1190–202. 19. C owell PD, Gia aglione JM, Jones AE, Nunley NM, Hashimo o T, Delcou AML, e al. MYC is a egula o o and ogen ecep o inhibi ion-induced me abolic equi emen s in p os a e cance . Cell Rep. 2023;42:113221. 20. Liu Y, Zuckie LS, Ghesani NV. Dominan up ake o a y acid o e glucose by p os a e cells: a po en ial new diagnos ic and he apeu ic app oach. An icance Res. 2010;30:369–74. 21. Sadeghi RN, Ka ami-Teh ani F, Salami S. Ta ge ing p os a e cance cell me a- bolism: impac o hexokinase and CPT-1 enzymes. Tumou Biol. 2015;36:2893–905. 22. Twum-Ampo o J, Fu D-X, Passani i A, Hussain A, Siddiqui MM. Me abolic a ge s o po en ial p os a e cance he apeu ics. Cu Opin Oncol. 2016;28:241–7. 23. Jad a H. PET o glucose me abolism and cellula p oli e a ion in p os a e cance . J Nucl Med. 2016;57:25S–9S. 24. Vaz CV, Al es MG, Ma ques R, Mo ei a PI, Oli ei a PF, Maia CJ, e al. And ogen- esponsi e and non esponsi e p os a e cance cells p esen a dis inc glycoly ic me abolism p ofile. In J Biochem Cell Biol. 2012;44:2077–84. 25. G anlund KL, Tee S-S, Va gas HA, Lyashchenko SK, Reznik E, Fine S, e al. Hype pola ized MRI o human p os a e cance e eals inc eased lac a e wi h umo g ade d i en by monoca boxyla e anspo e 1. Cell Me ab. 2020;31:105–14.e3. 26. Chen M-L, Xu P-Z, Peng X, Chen WS, Guzman G, Yang X, e al. The deficiency o Ak 1 is su ficien o supp ess umo de elopmen in P en +/−mice. Genes De . 2006;20:1569–74. 27. G asso CS, Wu YM, Robinson DR, Cao X, Dhanaseka an SM, Khan AP, e al. The mu a ional landscape o le hal cas a ion- esis an p os a e cance . Na u e. 2012;487:239–43. 28. Choi SYC, E inge SL, Lin D, Xue H, Ci X, Naba i N, e al. Ta ge ing MCT4 o educe lac ic acid sec e ion and glycolysis o ea men o neu oendoc ine p os a e cance . Cance Med. 2018;7:3385–92. 29. Po po a o PE, Filigheddu N, Ped o JMB-S, K oeme G, Galluzzi L. Mi ochond ial me abolism and cance . Cell Res. 2018;28:265–80. 30. Jia D, Lu M, Jung KH, Pa k JH, Yu L, Onuchic JN, e al. Elucida ing cance me abolic plas ici y by coupling gene egula ion wi h me abolic pa hways. P oc Na l Acad Sci USA. 2019;116:3909–18. 31. Cassim S, Vuče ićM, Žd ale ićM, Pouyssegu J. Wa bu g and beyond: he powe o mi ochond ial me abolism o collabo a e o eplace e men a i e glycolysis in cance . Cance s (Basel). 2020;12:1119. 32. G asso D, Zampie i LX, Capelôa T, Van de Velde JA, Son eaux P. Mi ochond ia in cance . Cell S ess. 2020;4:114–46. 33. Ro h KG, Mambe sa ie I, Kulka ni P, Salgia R. The mi ochond ion as an eme - ging he apeu ic a ge in cance . T ends Mol Med. 2020;26:119–34. 34. Mosie JA, Schwage SC, Boyajian DA, Reinha -King CA. Cance cell me abolic plas ici y in mig a ion and me as asis. Clin Exp Me as asis. 2021;38:343–59. 35. Tan YQ, Zhang X, Zhang S, Zhu T, Ga g M, Lobie PE, e al. Mi ochond ia: he me abolic swi ch o cellula oncogenic ans o ma ion. Biochim Biophys Ac a Re Cance . 2021;1876:188534. 36. Zhang X, Su Q, Zhou J, Yang Z, Liu Z, Ji L, e al. To be ay o o figh ? The dual iden i y o he mi ochond ia in cance . Fu u e Oncol. 2021;17:723–43. 37. Uo T, Ojo KK, Sp enge CCT, So iano Epilepsia K, Pe e a BGK, Damoda asamy, M e al. A Compound ha Inhibi s Glycolysis in P os a e Cance Con ols G ow h o Ad anced P os a e Cance . Mol Cance The . 2024; h ps://doi.o g/10.1158/1535- 7163.MCT-23-0540. 38. Ba man CR, Weiland DR, Shen Y, Lee WD, Han Y, TeSlaa T, e al. Slow TCA flux and ATP p oduc ion in p ima y solid umou s bu no me as ases. Na u e. 2023;614:349–57. 39. Fische GM, Jalali A, Ki che DA, Lee W-C, McQuade JL, Haydu LE, e al. Molecula p ofiling e eals unique immune and me abolic ea u es o melanoma b ain me as ases. Cance Disco . 2019;9:628–45. 40. Yap TA, Da e N, Mahend a M, Zhang J, Kamiya-Ma suoka C, Me ic-Be ns am F, e al. Complex I inhibi o o oxida i e phospho yla ion in ad anced solid umo s and acu e myeloid leukemia: phase I ials. Na Med. 2023;29:115–26. 41. Mullen AR, Hu Z, Shi X, Jiang L, Bo oughs LK, Ko acs Z, e al. Oxida ion o alpha- ke oglu a a e is equi ed o educ i e ca boxyla ion in cance cells wi h mi o- chond ial de ec s. Cell Rep. 2014;7:1679–90. 42. Tomlinson IPM, Alam NA, Rowan AJ, Ba clay E, Jaege EEM, Kelsell D, e al. Ge mline mu a ions in FH p edispose o dominan ly inhe i ed u e ine fib oids, skin leiomyoma a and papilla y enal cell cance . Na Gene . 2002;30:406–10. 43. Baysal BE, Fe ell RE, Wille -B ozick JE, Law ence EC, Myssio ek D, Bosch A, e al. Mu a ions in SDHD, a mi ochond ial complex II gene, in he edi a y pa a- ganglioma. Science. 2000;287:848–51. M. Pujana-Vaque izo e al. 1258 B i ish Jou nal o Cance (2024) 131:1250 – 1262