Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies

  1. Ambrosini, Giulia
  2. Cordani, Marco
  3. Zarrabi, Ali
  4. Alcon-Rodriguez, Sergio 1
  5. Sainz, Rosa M.
  6. Velasco, Guillermo
  7. Gonzalez-Menendez, Pedro
  8. Dando, Ilaria
  1. 1 Universidad de Oviedo (Departamento de Morfología y Biología Celular)
Revista:
Cell Communication and Signaling

ISSN: 1478-811X

Año de publicación: 2024

Volumen: 22

Número: 1

Tipo: Artículo

DOI: 10.1186/S12964-023-01462-0 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: Cell Communication and Signaling

Resumen

Prostate cancer, as one of the most prevalent malignancies in males, exhibits an approximate 5-year survival rate of 95% in advanced stages. A myriad of molecular events and mutations, including the accumulation of oncometabolites, underpin the genesis and progression of this cancer type. Despite growing research demonstrating the pivotal role of oncometabolites in supporting various cancers, including prostate cancer, the root causes of their accumulation, especially in the absence of enzymatic mutations, remain elusive. Consequently, identifying a tangible therapeutic target poses a formidable challenge. In this review, we aim to delve deeper into the implications of oncometabolite accumulation in prostate cancer. We center our focus on the consequential epigenetic alterations and impacts on cancer stem cells, with the ultimate goal of outlining novel therapeutic strategies.

Referencias bibliográficas

  • Ittmann M. Anatomy and histology of the human and murine prostate. Cold Spring Harb Perspect Med. 2018;8:a030346.
  • Sandhu S, Moore CM, Chiong E, Beltran H, Bristow RG, Williams SG. Prostate cancer. Lancet. 2021;398:1075–90.
  • Espiritu SMG, Liu LY, Rubanova Y, Bhandari V, Holgersen EM, Szyca LM, et al. The evolutionary landscape of localized prostate cancers drives clinical aggression. Cell. 2018;173:1003-1013.e15.
  • Rawla P. Epidemiology of prostate cancer. World J Oncol. 2019;10:63–89.
  • Hakozaki Y, Yamada Y, Kawai T, Nakamura M, Takeshima Y, Iwaki T, et al. Time to castration resistance is a novel prognostic factor of cancer-specific survival in patients with nonmetastatic castration-resistant prostate cancer. Sci Rep. 2022;12:16202.
  • Saad F, Bögemann M, Suzuki K, Shore N. Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors. Prostate Cancer Prostatic Dis. 2021;24:323–34.
  • Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. 2015;4:365–80.
  • Oh M, Alkhushaym N, Fallatah S, Althagafi A, Aljadeed R, Alsowaida Y, et al. The association of BRCA1 and BRCA2 mutations with prostate cancer risk, frequency, and mortality: a meta-analysis. Prostate. 2019;79:880–95.
  • Khosh Kish E, Choudhry M, Gamallat Y, Buharideen SM, D D, Bismar TA. The Expression of Proto-Oncogene ETS-Related Gene (ERG) plays a central role in the oncogenic mechanism involved in the development and progression of prostate cancer. Int J Mol Sci. 2022;23:4772.
  • Croonquist PA, Van Ness B. The polycomb group protein enhancer of zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype. Oncogene. 2005;24:6269–80.
  • Zoma M, Curti L, Shinde D, Albino D, Mitra A, Sgrignani J, et al. EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer. Nat Commun. 2021;12:4147.
  • Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338:1465–9.
  • Demichelis F, Rubin MA. TMPRSS2-ETS fusion prostate cancer: biological and clinical implications. J Clin Pathol. 2007;60:1185–6.
  • Yu J, Yu J, Mani R-S, Cao Q, Brenner CJ, Cao X, et al. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell. 2010;17:443–54.
  • Kachuri L, Hoffmann TJ, Jiang Y, Berndt SI, Shelley JP, Schaffer KR, et al. Genetically adjusted PSA levels for prostate cancer screening. Nat Med. 2023;29:1412–23.
  • Cirne F, Kappel C, Zhou S, Mukherjee SD, Dehghan M, Petropoulos J-A, et al. Modifiable risk factors for prostate cancer in low- and lower-middle-income countries: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2022;25:453–62.
  • Torrano V, Valcarcel-Jimenez L, Cortazar AR, Liu X, Urosevic J, Castillo-Martin M, et al. The metabolic co-regulator PGC1α suppresses prostate cancer metastasis. Nat Cell Biol. 2016;18:645–56.
  • Li Z, Low V, Luga V, Sun J, Earlie E, Parang B, et al. Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression. Nat Commun. 2022;13:6239.
  • Lautert-Dutra W, Dos Reis RB, Squire JA. Precision medicine for prostate cancer-improved outcome prediction for low-intermediate risk disease using a six-gene copy number alteration classifier. Br J Cancer. 2023;128:2163–4.
  • Saad F. Continuing to improve outcomes of men with metastatic prostate cancer. Nat Rev Clin Oncol. 2019;16:597–8.
  • Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46.
  • Pavlova NN, Zhu J, Thompson CB. The hallmarks of cancer metabolism: still emerging. Cell Metab. 2022;34:355–77.
  • Khatami F, Aghamir SMK, Tavangar SM. Oncometabolites: a new insight for oncology. Mol Genet Genomic Med. 2019;7:e873.
  • Sajnani K, Islam F, Smith RA, Gopalan V, Lam AK-Y. Genetic alterations in Krebs cycle and its impact on cancer pathogenesis. Biochimie. 2017;135:164–72.
  • Du X, Hu H. The roles of 2-hydroxyglutarate. Front Cell Dev Biol. 2021;9:651317.
  • Fan J, Teng X, Liu L, Mattaini KR, Looper RE, Vander Heiden MG, et al. Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate. ACS Chem Biol. 2015;10:510–6.
  • Galluzzi L, Kroemer G. Potent immunosuppressive effects of the oncometabolite R-2-hydroxyglutarate. OncoImmunology. 2018;7:e1528815.
  • Dando I, Pozza ED, Ambrosini G, Torrens-Mas M, Butera G, Mullappilly N, et al. Oncometabolites in cancer aggressiveness and tumour repopulation. Biol Rev Camb Philos Soc. 2019;94:1530–46.
  • Ippolito L, Comito G, Parri M, Iozzo M, Duatti A, Virgilio F, et al. Lactate rewires lipid metabolism and sustains a metabolic-epigenetic axis in prostate cancer. Can Res. 2022;82:1267–82.
  • Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, et al. Lactate metabolism in human lung tumors. Cell. 2017;171:358-371.e9.
  • Heid I, Münch C, Karakaya S, Lueong SS, Winkelkotte AM, Liffers ST, et al. Functional noninvasive detection of glycolytic pancreatic ductal adenocarcinoma. Cancer Metabol. 2022;10:24.
  • Longhitano L, Giallongo S, Orlando L, Broggi G, Longo A, Russo A, et al. Lactate rewrites the metabolic reprogramming of uveal melanoma cells and induces quiescence phenotype. Int J Mol Sci. 2023;24:24.
  • Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574:575–80.
  • Chen A-N, Luo Y, Yang Y-H, Fu J-T, Geng X-M, Shi J-P, et al. Lactylation, a novel metabolic reprogramming code: current status and prospects. Front Immunol. 2021;12:688910.
  • Yang Z, Yan C, Ma J, Peng P, Ren X, Cai S, et al. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma. Nat Metab. 2023;5:61–79.
  • Wang J, Mao L, Wang J, Zhang X, Wu M, Wen Q, et al. Beyond metabolic waste: lysine lactylation and its potential roles in cancer progression and cell fate determination. Cell Oncol. 2023;46:465–80.
  • Zabala-Letona A, Arruabarrena-Aristorena A, Martín-Martín N, Fernandez-Ruiz S, Sutherland JD, Clasquin M, et al. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature. 2017;547:109–13.
  • Chowdhury R, Yeoh KK, Tian Y-M, Hillringhaus L, Bagg EA, Rose NR, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12:463–9.
  • Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S-H, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17–30.
  • Li S-T, Huang D, Shen S, Cai Y, Xing S, Wu G, et al. Myc-mediated SDHA acetylation triggers epigenetic regulation of gene expression and tumorigenesis. Nat Metab. 2020;2:256–69.
  • Chen H, Zhu W, Li X, Xue L, Wang Z, Wu H. Genetic and epigenetic patterns in patients with the head-and-neck paragangliomas associate with differential clinical characteristics. J Cancer Res Clin Oncol. 2017;143:953–60.
  • He X, Yan B, Liu S, Jia J, Lai W, Xin X, et al. Chromatin remodeling factor LSH drives cancer progression by suppressing the activity of fumarate hydratase. Can Res. 2016;76:5743–55.
  • Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Seo SI, et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer. 2009;125:353–5.
  • Yang H, Liu Y, Bai F, Zhang J-Y, Ma S-H, Liu J, et al. Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene. 2013;32:663–9.
  • Xu H, Sun Y, You B, Huang CP, Ye D, Chang C. Androgen receptor reverses the oncometabolite R-2-hydroxyglutarate-induced prostate cancer cell invasion via suppressing the circRNA-51217/miRNA-646/TGFβ1/p-Smad2/3 signaling. Cancer Lett. 2020;472:151–64.
  • Saxena N, Beraldi E, Fazli L, Somasekharan SP, Adomat H, Zhang F, et al. Androgen receptor (AR) antagonism triggers acute succinate-mediated adaptive responses to reactivate AR signaling. EMBO Molec Med. 2021;13(5):e13427.
  • Quiros-Gonzalez I, Gonzalez-Menendez P, Mayo JC, Hevia D, Artime-Naveda F, Fernandez-Vega S, et al. Androgen-dependent prostate cancer cells reprogram their metabolic signature upon GLUT1 upregulation by manganese superoxide dismutase. Antioxidants (Basel). 2022;11:313.
  • Ippolito L, Morandi A, Taddei ML, Parri M, Comito G, Iscaro A, et al. Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer. Oncogene. 2019;38:5339–55.
  • Franko A, Shao Y, Heni M, Hennenlotter J, Hoene M, Hu C, et al. Human prostate cancer is characterized by an increase in urea cycle metabolites. Cancers. 2020;12:1814.
  • Gao Y, Chen L, Du Z, Gao W, Wu Z, Liu X, et al. Glutamate decarboxylase 65 signals through the androgen receptor to promote castration resistance in prostate cancer. Can Res. 2019;79:4638–49.
  • Rodrigo MAM, Strmiska V, Horackova E, Buchtelova H, Michalek P, Stiborova M, et al. Sarcosine influences apoptosis and growth of prostate cells via cell-type specific regulation of distinct sets of genes. Prostate. 2018;78:104–12.
  • Strmiska V, Michalek P, Lackova Z, Guran R, Krizkova S, Vanickova L, et al. Sarcosine is a prostate epigenetic modifier that elicits aberrant methylation patterns through the SAMe-Dnmts axis. Mol Oncol. 2019;13:1002–17.
  • Heger Z, Gumulec J, Cernei N, Polanska H, Raudenska M, Masarik M, et al. Relation of exposure to amino acids involved in sarcosine metabolic pathway on behavior of non-tumor and malignant prostatic cell lines. Prostate. 2016;76:679–90.
  • Delkov D, Yoanidu L, Tomov D, Stoyanova R, Dechev I, Uzunova Y. Oncometabolites in urine – a new opportunity for detection and prognosis of the clinical progress of verified prostate cancer-a pilot study. Turk J Med Sci. 2022;52(3):699–706.
  • Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Can Res. 2005;65:10946–51.
  • Wang X, Xu H, Cheng C, Ji Z, Zhao H, Sheng Y, et al. Identification of a Zeb1 expressing basal stem cell subpopulation in the prostate. Nat Commun. 2020;11:706.
  • Skvortsov S, Skvortsova I-I, Tang DG, Dubrovska A. Concise review: prostate cancer stem cells: current understanding. Stem Cells. 2018;36:1457–74.
  • Li JJ, Shen MM. Prostate stem cells and cancer stem cells. Cold Spring Harb Perspect Med. 2019;9:a030395.
  • Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017;14:611–29.
  • Stylianou N, Lehman ML, Wang C, Fard AT, Rockstroh A, Fazli L, et al. A molecular portrait of epithelial–mesenchymal plasticity in prostate cancer associated with clinical outcome. Oncogene. 2019;38:913–34.
  • Chaves LP, Melo CM, Saggioro FP, Reis RBD, Squire JA. Epithelial-mesenchymal transition signaling and prostate cancer stem cells: emerging biomarkers and opportunities for precision therapeutics. Genes (Basel). 2021;12:1900.
  • Grant CM, Kyprianou N. Epithelial mesenchymal transition (EMT) in prostate growth and tumor progression. Transl Androl Urol. 2013;2:20211–20211.
  • Sandsmark E, Hansen AF, Selnæs KM, Bertilsson H, Bofin AM, Wright AJ, et al. A novel non-canonical Wnt signature for prostate cancer aggressiveness. Oncotarget. 2016;8:9572–86.
  • Bisson I, Prowse DM. WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res. 2009;19:683–97.
  • Nath D, Li X, Mondragon C, Post D, Chen M, White JR, et al. Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling. Cell Commun Signal. 2019;17:120.
  • Karhadkar SS, Steven Bova G, Abdallah N, Dhara S, Gardner D, Maitra A, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004;431:707–12.
  • Chang H-H, Chen B-Y, Wu C-Y, Tsao Z-J, Chen Y-Y, Chang C-P, et al. Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model. J Biomed Sci. 2011;18:6.
  • Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, Castillo-Martin M, Quinn SA, Rodriguez-Barrueco R, et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell. 2012;22:373–88.
  • Stoyanova T, Riedinger M, Lin S, Faltermeier CM, Smith BA, Zhang KX, et al. Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2016;113:E6457–66.
  • Kwon O-J, Zhang L, Wang J, Su Q, Feng Q, Zhang XHF, et al. Notch promotes tumor metastasis in a prostate-specific Pten-null mouse model. J Clin Invest. 2016;126:2626–41.
  • Stopsack KH, Nandakumar S, Wibmer AG, Haywood S, Weg ES, Barnett ES, et al. Oncogenic genomic alterations, clinical phenotypes, and outcomes in metastatic castration-sensitive prostate cancer. Clin Cancer Res. 2020;26:3230–8.
  • Chen B, Zhang Y, Li C, Xu P, Gao Y, Xu Y. CNTN-1 promotes docetaxel resistance and epithelial-to-mesenchymal transition via the PI3K/Akt signaling pathway in prostate cancer. Arch Med Sci. 2021;17:152–65.
  • Peng Y, Zheng J, Zhou Y, Li J. Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-κB signaling pathway with distinct mechanisms. Acta Pharmacol Sin. 2013;34:939–50.
  • Jin R, Yi Y, Yull FE, Blackwell TS, Clark PE, Koyama T, et al. NF-κB gene signature predicts prostate cancer progression. Cancer Res. 2014;74:2763–72.
  • Gogola S, Rejzer M, Bahmad HF, Abou-Kheir W, Omarzai Y, Poppiti R. Epithelial-to-mesenchymal transition-related markers in prostate cancer: from bench to bedside. Cancers. 2023;15:2309.
  • Ruscetti M, Quach B, Dadashian EL, Mulholland DJ, Wu H. Tracking and functional characterization of epithelial-mesenchymal transition and mesenchymal tumor cells during prostate cancer metastasis. Can Res. 2015;75:2749–59.
  • Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature. 2007;447:433–40.
  • Shi Y. Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet. 2007;8:829–33.
  • Shi R, Liao C, Zhang Q. Hypoxia-driven effects in cancer: characterization, mechanisms, and therapeutic implications. Cells. 2021;10:678.
  • Naik PP, Panigrahi S, Parida R, Praharaj PP, Bhol CS, Patil S, et al. Metabostemness in cancer: linking metaboloepigenetics and mitophagy in remodeling cancer stem cells. Stem Cell Rev and Rep. 2022;18:198–213.
  • Baryła M, Semeniuk-Wojtaś A, Róg L, Kraj L, Małyszko M, Stec R. Oncometabolites—A link between cancer cells and tumor microenvironment. Biology. 2022;11:270.
  • Sciacovelli M, Gonçalves E, Johnson TI, Zecchini VR, da Costa ASH, Gaude E, et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature. 2016;537:544–7.
  • Lu J, Fei F, Wu C, Mei J, Xu J, Lu P. ZEB1: catalyst of immune escape during tumor metastasis. Biomed Pharmacother. 2022;153:113490.
  • Yu L, Liu S, Zhang C, Zhang B, Simoes BM, Eyre R, et al. Enrichment of human osteosarcoma stem cells based on hTERT transcriptional activity. Oncotarget. 2013;4:2326–38.
  • Zhang Y, Liu Y, Lang F, Yang C. IDH mutation and cancer stem cell. Essays Biochem. 2022;66:413–22.
  • Giafaglione JM, Crowell PD, Delcourt AML, Hashimoto T, Ha SM, Atmakuri A, et al. Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment. Nat Cell Biol. 2023;25:1821–32.
  • Ittmann M, Huang J, Radaelli E, Martin P, Signoretti S, Sullivan R, et al. Animal models of human prostate cancer: the consensus report of the New York meeting of the mouse models of human cancers consortium prostate pathology committee. Cancer Res. 2013;73:2718–36.
  • Slater M, Barden JA, Murphy CR. Changes in growth factor expression in the ageing prostate may disrupt epithelial-stromal homeostasis. Histochem J. 2000;32:357–64.
  • Shiao SL, Chu GC-Y, Chung LWK. Regulation of prostate cancer progression by the tumor microenvironment. Cancer Lett. 2016;380:340–8.
  • Chiarugi P, Paoli P, Cirri P. Tumor microenvironment and metabolism in prostate cancer. Semin Oncol. 2014;41:267–80.
  • Costello LC, Franklin RB. The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots. Mol Cancer. 2006;5:17.
  • Beier A-MK, Puhr M, Stope MB, Thomas C, Erb HHH. Metabolic changes during prostate cancer development and progression. J Cancer Res Clin Oncol. 2023;149:2259–70.
  • Darby S, Sahadevan K, Khan MM, Robson CN, Leung HY, Gnanapragasam VJ. Loss of Sef (similar expression to FGF) expression is associated with high grade and metastatic prostate cancer. Oncogene. 2006;25:4122–7.
  • Bedeschi M, Marino N, Cavassi E, Piccinini F, Tesei A. Cancer-associated fibroblast: role in prostate cancer progression to metastatic disease and therapeutic resistance. Cells. 2023;12:802.
  • Tuxhorn JA, Ayala GE, Rowley DR. Reactive stroma in prostate cancer progression. J Urol. 2001;166:2472–83.
  • Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD, Rowley DR. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin Cancer Res. 2002;8:2912–23.
  • Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3:349–63.
  • Mueller L, Goumas FA, Affeldt M, Sandtner S, Gehling UM, Brilloff S, et al. Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment. Am J Pathol. 2007;171:1608–18.
  • Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I, et al. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci U S A. 2010;107:20009–14.
  • Direkze NC, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res. 2004;64:8492–5.
  • Potenta S, Zeisberg E, Kalluri R. The role of endothelial-to-mesenchymal transition in cancer progression. Br J Cancer. 2008;99:1375–9.
  • Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med. 2007;13:952–61.
  • Radisky ES, Radisky DC. Stromal induction of breast cancer: inflammation and invasion. Rev Endocr Metab Disord. 2007;8:279–87.
  • Franco OE, Jiang M, Strand DW, Peacock J, Fernandez S, Jackson RS, et al. Altered TGF-β signaling in a subpopulation of human stromal cells promotes prostatic carcinogenesis. Cancer Res. 2011;71:1272–81.
  • Taylor RA, Toivanen R, Frydenberg M, Pedersen J, Harewood L, Australian Prostate Cancer Bioresource, et al. Human epithelial basal cells are cells of origin of prostate cancer, independent of CD133 status. Stem Cells. 2012;30:1087–96.
  • Russo G, Mischi M, Scheepens W, De la Rosette JJ, Wijkstra H. Angiogenesis in prostate cancer: onset, progression and imaging. BJU Int. 2012;110:E794-808.
  • Butler JM, Kobayashi H, Rafii S. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer. 2010;10:138–46.
  • Wang X, Lee SO, Xia S, Jiang Q, Luo J, Li L, et al. Endothelial cells enhance prostate cancer metastasis via IL-6→androgen receptor→TGF-β→MMP-9 signals. Mol Cancer Ther. 2013;12:1026–37.
  • Godoy A, Montecinos VP, Gray DR, Sotomayor P, Yau JM, Vethanayagam RR, et al. Androgen deprivation induces rapid involution and recovery of human prostate vasculature. Am J Physiol Endocrinol Metab. 2011;300:E263-275.
  • Fidelito G, Watt MJ, Taylor RA. Personalized medicine for prostate cancer: is targeting metabolism a reality? Front Oncol. 2021;11:778761.
  • Gonzalez-Menendez P, Hevia D, Mayo JC, Sainz RM. The dark side of glucose transporters in prostate cancer: are they a new feature to characterize carcinomas? Int J Cancer. 2018;142:2414–24.
  • Gonzalez-Menendez P, Hevia D, Alonso-Arias R, Alvarez-Artime A, Rodriguez-Garcia A, Kinet S, et al. GLUT1 protects prostate cancer cells from glucose deprivation-induced oxidative stress. Redox Biol. 2018;17:112–27.
  • Li J, Ayene R, Ward KM, Dayanandam E, Ayene IS. Glucose deprivation increases nuclear DNA repair protein Ku and resistance to radiation induced oxidative stress in human cancer cells. Cell Biochem Funct. 2009;27:93–101.
  • De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7:256–69.
  • Martori C, Sanchez-Moral L, Paul T, Pardo JC, Font A, de RuizPorras V, et al. Macrophages as a therapeutic target in metastatic prostate cancer: a way to overcome immunotherapy resistance? Cancers (Basel). 2022;14:440.
  • de Bono JS, Guo C, Gurel B, De Marzo AM, Sfanos KS, Mani RS, et al. Prostate carcinogenesis: inflammatory storms. Nat Rev Cancer. 2020;20:455–69.
  • De Nunzio C, Kramer G, Marberger M, Montironi R, Nelson W, Schröder F, et al. The controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. Eur Urol. 2011;60:106–17.
  • Corzo CA, Condamine T, Lu L, Cotter MJ, Youn J-I, Cheng P, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207:2439–53.
  • Zhuang J, Zhang J, Lwin ST, Edwards JR, Edwards CM, Mundy GR, et al. Osteoclasts in multiple myeloma are derived from Gr-1+CD11b+myeloid-derived suppressor cells. PLoS ONE. 2012;7:e48871.
  • Hu C, Pang B, Lin G, Zhen Y, Yi H. Energy metabolism manipulates the fate and function of tumour myeloid-derived suppressor cells. Br J Cancer. 2020;122:23–9.
  • Koinis F, Xagara A, Chantzara E, Leontopoulou V, Aidarinis C, Kotsakis A. Myeloid-derived suppressor cells in prostate cancer: present knowledge and future perspectives. Cells. 2022;11:20.
  • Consiglio CR, Udartseva O, Ramsey KD, Bush C, Gollnick SO. Enzalutamide, an androgen receptor antagonist, enhances myeloid cell-mediated immune suppression and tumor progression. Cancer Immunol Res. 2020;8:1215–27.
  • Ludwig M, Rajvansh R, Drake JM. Emerging role of extracellular vesicles in prostate cancer. Endocrinology. 2021;162:bqab139.
  • Gaglani S, Gonzalez-Kozlova E, Lundon DJ, Tewari AK, Dogra N, Kyprianou N. Exosomes as a next-generation diagnostic and therapeutic tool in prostate cancer. Int J Mol Sci. 2021;22:10131.
  • Gao F, Xu Q, Tang Z, Zhang N, Huang Y, Li Z, et al. Exosomes derived from myeloid-derived suppressor cells facilitate castration-resistant prostate cancer progression via S100A9/circMID1/miR-506-3p/MID1. J Transl Med. 2022;20:346.
  • Xu F, Wang X, Huang Y, Zhang X, Sun W, Du Y, et al. Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8+ T cell. Cell Rep. 2023;42:113424.
  • Wang Z-H, Peng W-B, Zhang P, Yang X-P, Zhou Q. Lactate in the tumour microenvironment: from immune modulation to therapy. EBioMedicine. 2021;73:103627.
  • Li X, Yang Y, Zhang B, Lin X, Fu X, An Y, et al. Lactate metabolism in human health and disease. Sig Transduct Target Ther. 2022;7:1–22.
  • Sonveaux P, Végran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118:3930–42.
  • Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, et al. Glucose feeds the TCA cycle via circulating lactate. Nature. 2017;551:115–8.
  • Li F, Simon MC. Cancer cells don’t live alone: metabolic communication within tumor microenvironments. Dev Cell. 2020;54:183–95.
  • Doldi V, Callari M, Giannoni E, D’Aiuto F, Maffezzini M, Valdagni R, et al. Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation. Oncotarget. 2015;6:31441–60.
  • Valencia T, Kim JY, Abu-Baker S, Moscat-Pardos J, Ahn CS, Reina-Campos M, et al. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell. 2014;26:121–35.
  • Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De Donatis A, et al. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res. 2012;72:5130–40.
  • Pértega-Gomes N, Vizcaíno JR, Attig J, Jurmeister S, Lopes C, Baltazar F. A lactate shuttle system between tumour and stromal cells is associated with poor prognosis in prostate cancer. BMC Cancer. 2014;14:352.
  • Giannoni E, Taddei ML, Morandi A, Comito G, Calvani M, Bianchini F, et al. Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs oxphos and prostate cancer metastatic spread. Oncotarget. 2015;6:24061–74.
  • Choi SYC, Xue H, Wu R, Fazli L, Lin D, Collins CC, et al. The MCT4 gene: a novel, potential target for therapy of advanced prostate cancer. Clin Cancer Res. 2016;22:2721–33.
  • Pereira-Nunes A, Simões-Sousa S, Pinheiro C, Miranda-Gonçalves V, Granja S, Baltazar F. Targeting lactate production and efflux in prostate cancer. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165894.
  • El-Kenawi A, Gatenbee C, Robertson-Tessi M, Bravo R, Dhillon J, Balagurunathan Y, et al. Acidity promotes tumour progression by altering macrophage phenotype in prostate cancer. Br J Cancer. 2019;121:556–66.
  • Chaudagar K, Hieromnimon HM, Khurana R, Labadie B, Hirz T, Mei S, et al. Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer. Clin Cancer Res. 2023;29:1952–68.
  • Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, et al. Ketones and lactate “fuel” tumor growth and metastasis: evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle. 2010;9:3506–14.
  • Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, et al. Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment. Int J Biochem Cell Biol. 2011;43:1045–51.
  • Luo G, He Y, Yu X. Bone marrow adipocyte: an intimate partner with tumor cells in bone metastasis. Front Endocrinol (Lausanne). 2018;9:339.
  • Cutruzzolà F, Giardina G, Marani M, Macone A, Paiardini A, Rinaldo S, et al. Glucose metabolism in the progression of prostate cancer. Front Physiol. 2017;8:97.
  • Diedrich JD, Rajagurubandara E, Herroon MK, Mahapatra G, Hüttemann M, Podgorski I. Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation. Oncotarget. 2016;7:64854–77.
  • Whitburn J, Rao SR, Morris EV, Tabata S, Hirayama A, Soga T, et al. Metabolic profiling of prostate cancer in skeletal microenvironments identifies G6PD as a key mediator of growth and survival. Sci Adv. 2022;8:eabf9096.
  • Richman EL, Kenfield SA, Stampfer MJ, Giovannucci EL, Zeisel SH, Willett WC, et al. Choline intake and risk of lethal prostate cancer: incidence and survival123. Am J Clin Nutr. 2012;96:855–63.
  • Mori N, Wildes F, Takagi T, Glunde K, Bhujwalla ZM. The tumor microenvironment modulates choline and lipid metabolism. Front Oncol. 2016;6:262.
  • Vykoukal J, Fahrmann JF, Gregg JR, Tang Z, Basourakos S, Irajizad E, et al. Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer. Nat Commun. 2020;11:4279.
  • Siltari A, Syvälä H, Lou Y-R, Gao Y, Murtola TJ. Role of lipids and lipid metabolism in prostate cancer progression and the tumor’s immune environment. Cancers (Basel). 2022;14:4293.
  • Neuwirt H, Bouchal J, Kharaishvili G, Ploner C, Jöhrer K, Pitterl F, et al. Cancer-associated fibroblasts promote prostate tumor growth and progression through upregulation of cholesterol and steroid biosynthesis. Cell Commun Signal. 2020;18:11.
  • Mishra R, Haldar S, Placencio V, Madhav A, Rohena-Rivera K, Agarwal P, et al. Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. J Clin Invest. 2018;128:4472–84.
  • Matos A, Carvalho M, Bicho M, Ribeiro R. Arginine and arginases modulate metabolism, tumor microenvironment and prostate cancer progression. Nutrients. 2021;13:4503.
  • Tsai C-S, Chen F-H, Wang C-C, Huang H-L, Jung S-M, Wu C-J, et al. Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth. Int J Radiat Oncol Biol Phys. 2007;68:499–507.
  • Gannon PO, Godin-Ethier J, Hassler M, Delvoye N, Aversa M, Poisson AO, et al. Androgen-regulated expression of arginase 1, arginase 2 and interleukin-8 in human prostate cancer. PLoS ONE. 2010;5:e12107.
  • Bronte V, Kasic T, Gri G, Gallana K, Borsellino G, Marigo I, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med. 2005;201:1257–68.
  • Cimen Bozkus C, Elzey BD, Crist SA, Ellies LG, Ratliff TL. Expression of cationic amino acid transporter 2 is required for myeloid-derived suppressor cell-mediated control of T cell immunity. J Immunol. 2015;195:5237–50.
  • Hossain DMS, Pal SK, Moreira D, Duttagupta P, Zhang Q, Won H, et al. TLR9-targeted STAT3 silencing abrogates immunosuppressive activity of myeloid-derived suppressor cells from prostate cancer patients. Clin Cancer Res. 2015;21:3771–82.
  • Zhunussova A, Sen B, Friedman L, Tuleukhanov S, Brooks AD, Sensenig R, et al. Tumor microenvironment promotes dicarboxylic acid carrier-mediated transport of succinate to fuel prostate cancer mitochondria. Am J Cancer Res. 2015;5:1665–79.
  • Sant’Anna-Silva ACB, Perez-Valencia JA, Sciacovelli M, Lalou C, Sarlak S, Tronci L, et al. Succinate anaplerosis has an onco-driving potential in prostate cancer cells. Cancers (Basel). 2021;13:1727.
  • Zhao H, Yang L, Baddour J, Achreja A, Bernard V, Moss T, et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife. 2016;5:e10250.
  • Deshmukh A, Deshpande K, Arfuso F, Newsholme P, Dharmarajan A. Cancer stem cell metabolism: a potential target for cancer therapy. Mol Cancer. 2016;15:69.
  • Sancho P, Barneda D, Heeschen C. Hallmarks of cancer stem cell metabolism. Br J Cancer. 2016;114:1305–12.
  • Della Sala G, Pacelli C, Agriesti F, Laurenzana I, Tucci F, Tamma M, et al. Unveiling metabolic vulnerability and plasticity of human osteosarcoma stem and differentiated cells to improve cancer therapy. Biomedicines. 2021;10:28.
  • Ren L, Ruiz-Rodado V, Dowdy T, Huang S, Issaq SH, Beck J, et al. Glutaminase-1 (GLS1) inhibition limits metastatic progression in osteosarcoma. Cancer Metab. 2020;8:4.
  • Lai HW, Kasai M, Yamamoto S, Fukuhara H, Karashima T, Kurabayashi A, et al. Metabolic shift towards oxidative phosphorylation reduces cell-density-induced cancer-stem-cell-like characteristics in prostate cancer in vitro. Biol Open. 2023;12:bio059615.
  • Reznik E, Luna A, Aksoy BA, Liu EM, La K, Ostrovnaya I, et al. A landscape of metabolic variation across tumor types. Cell Syst. 2018;6:301-313.e3.
  • Rodrigues AS, Pereira SL, Ramalho-Santos J. Stem metabolism: insights from oncometabolism and vice versa. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165760.
  • Yamamoto T, Hatabayashi K, Arita M, Yajima N, Takenaka C, Suzuki T, et al. Kynurenine signaling through the aryl hydrocarbon receptor maintains the undifferentiated state of human embryonic stem cells. Sci Signal. 2019;12:eaaw3306.
  • Qiu S, Cai Y, Yao H, Lin C, Xie Y, Tang S, et al. Small molecule metabolites: discovery of biomarkers and therapeutic targets. Signal Transduct Target Ther. 2023;8(1):132.
  • Struck-Lewicka W, Kordalewska M, Bujak R, Yumba Mpanga A, Markuszewski M, Jacyna J, et al. Urine metabolic fingerprinting using LC-MS and GC-MS reveals metabolite changes in prostate cancer: a pilot study. J Pharm Biomed Anal. 2015;11(1):351–61.
  • Beyoğlu D, Idle JR. Metabolic rewiring and the characterization of oncometabolites. Cancers. 2021;13(12):2900.
  • Gouasmi R, Ferraro-Peyret C, Nancey S, Coste I, Renno T, Chaveroux C, et al. The kynurenine pathway and cancer: why keep it simple when you can make it complicated. Cancers. 2022;14(11):2793.
  • Ahmad F, Cherukuri MK, Choyke PL. Metabolic reprogramming in prostate cancer. Br J Cancer. 2021;125:1185–96.
  • Lynch MJ, Nicholson JK. Proton MRS of human prostatic fluid: correlations between citrate, spermine, and myo-inositol levels and changes with disease. Prostate. 1997;30(4):248–55.
  • Kline EE, Treat EG, Averna TA, Davis MS, Smith AY, Sillerud LO. Citrate concentrations in human seminal fluid and expressed prostatic fluid determined via 1H nuclear magnetic resonance spectroscopy outperform prostate specific antigen in prostate cancer detection. J Urol. 2006;176(5):2274–9.
  • Serkova NJ, Gamito EJ, Jones RH, O’Donnell C, Brown JL, Green S, et al. The metabolites citrate, myo-inositol, and spermine are potential age-independent markers of prostate cancer in human expressed prostatic secretions. Prostate. 2008;68(6):620–8.
  • Averna TA, Kline EE, Smith AY, Sillerud LO. A decrease in 1H nuclear magnetic resonance spectroscopically determined citrate in human seminal fluid accompanies the development of prostate adenocarcinoma. JUrol. 2005;173(2):433–8.
  • Tessem MB, Bertilsson H, Angelsen A, Bathen TF, Drabløs F, Rye MB. A balanced tissue composition reveals new metabolic and gene expression markers in prostate cancer. PLoS ONE. 2016;11(4):e0153727.
  • Tessem MB, Swanson MG, Keshari KR, Albers MJ, Joun D, Tabatabai ZL, et al. Evaluation of lactate and alanine as metabolic biomarkers of prostate cancer using 1H HR-MAS spectroscopy of biopsy tissues. Magn Reson Med. 2008;60(3):510–6.
  • Ramirez-Garrastacho M, Bajo-Santos C, Line A, Martens-Uzunova ES, de la Fuente JM, Moros M, et al. Extracellular vesicles as a source of prostate cancer biomarkers in liquid biopsies: a decade of research. Br J Cancer. 2021.
  • Clos-Garcia M, Loizaga-Iriarte A, Zuñiga-Garcia P, Sánchez-Mosquera P, Rosa Cortazar A, González E, et al. Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression. J Extracell Vesicles. 2018;7(1):1470442.
  • Palviainen M, Laukkanen K, Tavukcuoglu Z, Velagapudi V, Kärkkäinen O, Hanhineva K, et al. Cancer alters the metabolic fingerprint of extracellular vesicles. Cancers. 2020;12(11):3292.
  • Flavin R, Zadra G, Loda M. Metabolic alterations and targeted therapies in prostate cancer. J Pathol. 2011;223:284–95.
  • Czernin J, Benz MR, Allen-Auerbach MS. PET imaging of prostate cancer using 11 C-Acetate. Positron Emission Tomography. 2009;4:163–72.
  • Zadra G, Loda M. Metabolic vulnerabilities of prostate cancer: diagnostic and therapeutic opportunities. Cold Spring Harb Perspect Med. 2018;8:a030569.
  • Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2011;481:385–8.
  • Bader DA, Hartig SM, Putluri V, Foley C, Hamilton MP, Smith EA, et al. Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer. Nat Metabol. 2018;2018(1):70–85.
  • Molina JR, Sun Y, Protopopova M, Gera S, Bandi M, Bristow C, et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat Med. 2018;24:1036–46.
  • Naguib A, Mathew G, Reczek CR, Watrud K, Ambrico A, Herzka T, et al. Mitochondrial complex I inhibitors expose a vulnerability for selective killing of Pten-null cells. Cell Rep. 2018;23(1):58–67.
  • Roy S, Malone S, Grimes S, Morgan SC. Impact of concomitant medications on biochemical outcome in localised prostate cancer treated with radiotherapy and androgen deprivation therapy. Clin Oncol. 2021;33(3):181–90.
  • Nguyen MM, Martinez JA, Hsu CH, Sokoloff M, Krouse RS, Gibson BA, et al. Bioactivity and prostate tissue distribution of metformin in a preprostatectomy prostate cancer cohort. Eur J Cancer Prev. 2018;27(6):557–62.
  • Zaidi S, Gandhi J, Joshi G, Smith NL, Khan SA. The anticancer potential of metformin on prostate cancer. Prostate Cancer Prostatic Dis. 2019;22(3):351–61.
  • Sahra IB, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, et al. Targeting cancer cell metabolism: The combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res. 2010;70(6):2465–75.
  • Zadra G, Photopoulos C, Tyekucheva S, Heidari P, Weng QP, Fedele G, et al. A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis. EMBO Mol Med. 2014;6(4):519–38.
  • Chen HW, Chang YF, Chuang HY, Tai WT, Hwang JJ. Targeted therapy with fatty acid synthase inhibitors in a human prostate carcinoma LNCaP/tk-luc-bearing animal model. Prostate Cancer Prostatic Dis. 2012;15(3):260–4.
  • Ventura R, Mordec K, Waszczuk J, Wang Z, Lai J, Fridlib M, et al. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine. 2015;2(8):808–24.
  • Guth A, Monk E, Agarwal R, Bergman BC, Zemski-Berry KA, Minic A, et al. Targeting fat oxidation in mouse prostate cancer decreases tumor growth and stimulates anti-cancer immunity. Int J Mol Sci. 2020;21:9660.
  • Flaig TW, Salzmann-Sullivan M, Su LJ, Zhang Z, Joshi M, Gijón MA, et al. Lipid catabolism inhibition sensitizes prostate cancer cells to antiandrogen blockade. Oncotarget. 2017;8(34):56051–65.
  • Myint ZW, Sun RC, Hensley PJ, James AC, Wang P, Strup SE, et al. Evaluation of glutaminase expression in prostate adenocarcinoma and correlation with clinicopathologic parameters. Cancers. 2021;13(9):2157.
  • Zhao SG, Chen WS, Li H, Foye A, Zhang M, Sjöström M, et al. The DNA methylation landscape of advanced prostate cancer. Nat Genet. 2020;52(8):778–89.
  • Crispo F, Pietrafesa M, Condelli V, Maddalena F, Bruno G, Piscazzi A, et al. IDH1 targeting as a new potential option for intrahepatic cholangiocarcinoma treatment-current state and future perspectives. Molecules. 2020;25:3754.
  • Sumbly V, Landry I, Rizzo V. Ivosidenib for IDH1 mutant cholangiocarcinoma: a narrative review. Cureus. 2022;14:e21018.
  • Adeva J. Current development and future perspective of IDH1 inhibitors in cholangiocarcinoma. Liver Cancer Int. 2022;3:17–31.
  • Mellinghoff IK, van den Bent MJ, Blumenthal DT, Touat M, Peters KB, Clarke J, et al. Vorasidenib in IDH1- or IDH2-mutant low-grade glioma. N Engl J Med. 2023;389:589–601.
  • Tanabe S, Quader S, Cabral H, Ono R. Interplay of EMT and CSC in cancer and the potential therapeutic strategies. Front Pharmacol. 2020;11:904.
  • Jayachandran A, Dhungel B, Steel JC. Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma. J Hematol Oncol. 2016;9:74.
  • Chaves LP, Melo CM, Saggioro FP, dos Reis RB, Squire JA. Epithelial-mesenchymal transition signaling and prostate cancer stem cells: emerging biomarkers and opportunities for precision therapeutics. Genes. 2021;12:1900.
  • Tomacha J, Dokduang H, Padthaisong S, Namwat N, Klanrit P, Phetcharaburanin J, et al. Targeting fatty acid synthase modulates metabolic pathways and inhibits cholangiocarcinoma cell progression. Front Pharmacol. 2021;12:696961.
  • Kitagawa A, Osawa T, Noda M, Kobayashi Y, Aki S, Nakano Y, et al. Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma. Br J Cancer. 2023;128:2206–17.