Abstract
Metastasis formation is a complex process, involving multiple crucial steps, which are controlled by different regulatory mechanisms. In this context, the contribution of cancer metabolism to the metastatic cascade is being increasingly recognized. This Review focuses on changes in lipid metabolism that contribute to metastasis formation in solid tumors. We discuss the molecular mechanisms by which lipids induce a pro-metastatic phenotype and explore the role of lipids in response to oxidative stress and as signaling molecules. Finally, we reflect on potential avenues to target lipid metabolism to improve the treatment of metastatic cancers.
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References
Peck, B. & Schulze, A. Lipid metabolism at the nexus of diet and tumor microenvironment. Trends Cancer 5, 693–703 (2019).
Snaebjornsson, M. T., Janaki-Raman, S. & Schulze, A. Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer. Cell Metab. 31, 62–76 (2020).
Fahy, E. et al. A comprehensive classification system for lipids. J. Lipid Res. 46, 839–861 (2005).
Liebisch, G. et al. Update on LIPID MAPS classification, nomenclature, and shorthand notation for MS-derived lipid structures. J. Lipid Res. 61, 1539–1555 (2020).
Koundouros, N. & Poulogiannis, G. Reprogramming of fatty acid metabolism in cancer. Br. J. Cancer 122, 4–22 (2020).
Broadfield, L. A., Pane, A. A., Talebi, A., Swinnen, J. V. & Fendt, S. M. Lipid metabolism in cancer: new perspectives and emerging mechanisms. Dev. Cell 56, 1363–1393 (2021).
Harayama, T. & Riezman, H. Understanding the diversity of membrane lipid composition. Nat. Rev. Mol. Cell Biol. 19, 281–296 (2018).
Mollinedo, F. & Gajate, C. Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy: Thematic Review Series: Biology of Lipid Rafts. J. Lipid Res. 61, 611–635 (2020).
Menendez, J. A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 7, 763–777 (2007).
Rysman, E. et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res. 70, 8117–8126 (2010).
Porstmann, T. et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236 (2008).
Gouw, A. M. et al. The MYC oncogene cooperates with sterol-regulated element-binding protein to regulate lipogenesis essential for neoplastic growth. Cell Metab. 30, 556–572 (2019).
Griffiths, B. et al. Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth. Cancer Metab. 1, 3 (2013).
Williams, K. J. et al. An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity. Cancer Res. 73, 2550–2562 (2013).
Bi, J. et al. Oncogene amplification in growth factor signaling pathways renders cancers dependent on membrane lipid remodeling. Cell Metab. 30, 525–538 (2019).
Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41–45 (2017).
Acharya, R., Shetty, S. S. & Kumari, N. S. Fatty acid transport proteins (FATPs) in cancer. Chem. Phys. Lipids 250, 105269 (2023).
Bensaad, K. et al. Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep. 9, 349–365 (2014).
Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17, 1498–1503 (2011).
Olzmann, J. A. & Carvalho, P. Dynamics and functions of lipid droplets. Nat. Rev. Mol. Cell Biol. 20, 137–155 (2019).
Petan, T., Jarc, E. & Jusovic, M. Lipid droplets in cancer: guardians of fat in a stressful world. Molecules 23, 1941 (2018).
Cruz, A. L. S., Barreto, E. A., Fazolini, N. P. B., Viola, J. P. B. & Bozza, P. T. Lipid droplets: platforms with multiple functions in cancer hallmarks. Cell Death Dis. 11, 105 (2020).
Li, J. et al. Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene 35, 6378–6388 (2016).
Yue, S. et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab. 19, 393–406 (2014).
Geng, F. et al. Inhibition of SOAT1 suppresses glioblastoma growth via blocking SREBP-1-mediated lipogenesis. Clin. Cancer Res. 22, 5337–5348 (2016).
Ogretmen, B. Sphingolipid metabolism in cancer signalling and therapy. Nat. Rev. Cancer 18, 33–50 (2018).
Nagahashi, M. et al. Targeting the SphK1/S1P/S1PR1 axis that links obesity, chronic inflammation, and breast cancer metastasis. Cancer Res. 78, 1713–1725 (2018).
Arseni, L. et al. Sphingosine-1-phosphate recruits macrophages and microglia and induces a pro-tumorigenic phenotype that favors glioma progression. Cancers 15, 479 (2023).
van der Weyden, L. et al. Genome-wide in vivo screen identifies novel host regulators of metastatic colonization. Nature 541, 233–236 (2017).
Weigel, C. et al. Sphingosine kinase 2 in stromal fibroblasts creates a hospitable tumor microenvironment in breast cancer. Cancer Res. 83, 553–567 (2023).
Brinkmann, V. et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 9, 883–897 (2010).
Mullen, P. J., Yu, R., Longo, J., Archer, M. C. & Penn, L. Z. The interplay between cell signalling and the mevalonate pathway in cancer. Nat. Rev. Cancer 16, 718–731 (2016).
Shimano, H. & Sato, R. SREBP-regulated lipid metabolism: convergent physiology — divergent pathophysiology. Nat. Rev. Endocrinol. 13, 710–730 (2017).
Simons, K. & Gerl, M. J. Revitalizing membrane rafts: new tools and insights. Nat. Rev. Mol. Cell Biol. 11, 688–699 (2010).
Wang, M. & Casey, P. J. Protein prenylation: unique fats make their mark on biology. Nat. Rev. Mol. Cell Biol. 17, 110–122 (2016).
Freed-Pastor, W. A. et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148, 244–258 (2012).
Kaymak, I. et al. Mevalonate pathway provides ubiquinone to maintain pyrimidine synthesis and survival in p53-deficient cancer cells exposed to metabolic stress. Cancer Res. 80, 189–203 (2020).
McGregor, G. H. et al. Targeting the metabolic response to statin-mediated oxidative stress produces a synergistic antitumor response. Cancer Res. 80, 175–188 (2020).
Zhang, K. L. et al. Organ-specific cholesterol metabolic aberration fuels liver metastasis of colorectal cancer. Theranostics 11, 6560–6572 (2021).
Suresh, S. et al. Identifying the transcriptional drivers of metastasis embedded within localized melanoma. Cancer Discov. 13, 194–215 (2023).
Dorsch, M. et al. Statins affect cancer cell plasticity with distinct consequences for tumor progression and metastasis. Cell Rep. 37, 110056 (2021).
Longo, J., van Leeuwen, J. E., Elbaz, M., Branchard, E. & Penn, L. Z. Statins as anticancer agents in the era of precision medicine. Clin. Cancer Res. 26, 5791–5800 (2020).
Massague, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).
Obenauf, A. C. & Massague, J. Surviving at a distance: organ-specific metastasis. Trends Cancer 1, 76–91 (2015).
Tasdogan, A., Ubellacker, J. M. & Morrison, S. J. Redox regulation in cancer cells during metastasis. Cancer Discov. 11, 2682–2692 (2021).
Cheung, E. C. & Vousden, K. H. The role of ROS in tumour development and progression. Nat. Rev. Cancer 22, 280–297 (2022).
Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186–191 (2015).
Quintana, E. et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008).
Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).
Klein, C. A. Cancer progression and the invisible phase of metastatic colonization. Nat. Rev. Cancer 20, 681–694 (2020).
Werner-Klein, M. et al. Genetic alterations driving metastatic colony formation are acquired outside of the primary tumour in melanoma. Nat. Commun. 9, 595 (2018).
Iacobuzio-Donahue, C. A., Litchfield, K. & Swanton, C. Intratumor heterogeneity reflects clinical disease course. Nat. Cancer 1, 3–6 (2020).
Welch, D. R. & Hurst, D. R. Defining the hallmarks of metastasis. Cancer Res. 79, 3011–3027 (2019).
Bergers, G. & Fendt, S. M. The metabolism of cancer cells during metastasis. Nat. Rev. Cancer 21, 162–180 (2021).
Elia, I., Doglioni, G. & Fendt, S. M. Metabolic hallmarks of metastasis formation. Trends Cell Biol. 28, 673–684 (2018).
Faubert, B., Solmonson, A. & DeBerardinis, R. J. Metabolic reprogramming and cancer progression. Science 368, eaaw5473 (2020).
Pascual, G., Dominguez, D. & Benitah, S. A. The contributions of cancer cell metabolism to metastasis. Dis. Model. Mech. 11, dmm032920 (2018).
Dirat, B. et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 71, 2455–2465 (2011).
Jin, X. et al. A metastasis map of human cancer cell lines. Nature 588, 331–336 (2020).
Ferraro, G. B. et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nat. Cancer 2, 414–428 (2021).
Shen, D. et al. E2F1 promotes proliferation and metastasis of clear cell renal cell carcinoma via activation of SREBP1-dependent fatty acid biosynthesis. Cancer Lett. 514, 48–62 (2021).
Zaytseva, Y. Y. et al. Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res. 72, 1504–1517 (2012).
Du, Q. et al. FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis. Cell Death Dis. 13, 488 (2022).
Pascual, G. et al. Dietary palmitic acid promotes a prometastatic memory via Schwann cells. Nature 599, 485–490 (2021).
Li, Y. et al. Hepatic lipids promote liver metastasis. JCI Insight 5, e136215 (2020).
Yang, P. et al. CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis. Nat. Commun. 13, 5782 (2022).
Rambow, F. et al. Toward minimal residual disease-directed therapy in melanoma. Cell 174, 843–855 (2018).
Ubellacker, J. M. et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature 585, 113–118 (2020).
Vivas-Garcia, Y. et al. Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity. Mol. Cell 77, 120–137 (2020).
Tanaka, K. et al. ELOVL2 promotes cancer progression by inhibiting cell apoptosis in renal cell carcinoma. Oncol. Rep. 47, 23 (2022).
Chen, G. et al. Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target. Clin. Cancer Res. 20, 5537–5546 (2014).
Kang, Y. P. et al. Spheroid-induced epithelial–mesenchymal transition provokes global alterations of breast cancer lipidome: a multi-layered omics analysis. Front. Oncol. 9, 145 (2019).
Centenera, M. M. et al. ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer. Cancer Res. 81, 1704–1718 (2021).
Carracedo, A., Cantley, L. C. & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nat. Rev. Cancer 13, 227–232 (2013).
Davis, R. T. et al. Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing. Nat. Cell Biol. 22, 310–320 (2020).
Quan, J. et al. Acyl-CoA synthetase long-chain 3-mediated fatty acid oxidation is required for TGFβ1-induced epithelial–mesenchymal transition and metastasis of colorectal carcinoma. Int. J. Biol. Sci. 18, 2484–2496 (2022).
Lee, C. K. et al. Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation. Science 363, 644–649 (2019).
Huang, Y. et al. Ct-OATP1B3 promotes high-grade serous ovarian cancer metastasis by regulation of fatty acid β-oxidation and oxidative phosphorylation. Cell Death Dis. 13, 556 (2022).
van Weverwijk, A. et al. Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation. Nat. Commun. 10, 2698 (2019).
Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011).
Nath, A. & Chan, C. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers. Sci. Rep. 6, 18669 (2016).
Wang, Y. N. et al. CPT1A-mediated fatty acid oxidation promotes colorectal cancer cell metastasis by inhibiting anoikis. Oncogene 37, 6025–6040 (2018).
Schlaepfer, I. R. et al. Lipid catabolism via CPT1 as a therapeutic target for prostate cancer. Mol. Cancer Ther. 13, 2361–2371 (2014).
Loo, S. Y. et al. Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer. Sci. Adv. 7, eabh2443 (2021).
Altea-Manzano, P. et al. A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling. Nat. Cancer 4, 344–364 (2023).
Huang, D. et al. HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep. 8, 1930–1942 (2014).
Parida, P. K. et al. Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases. Nat. Cancer 4, 893–907 (2023).
Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).
Yang, W. S. & Stockwell, B. R. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem. Biol. 15, 234–245 (2008).
Conrad, M. et al. Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev. 32, 602–619 (2018).
Dixon, S. J. & Stockwell, B. R. The hallmarks of ferroptosis. Ann. Rev. Cancer Biol. 3, 35–54 (2019).
Friedmann Angeli, J. P., Miyamoto, S. & Schulze, A. Ferroptosis: the greasy side of cell death. Chem. Res. Toxicol. 32, 362–369 (2019).
Jiang, X., Stockwell, B. R. & Conrad, M. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266–282 (2021).
Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81–90 (2017).
Magtanong, L., Ko, P. J. & Dixon, S. J. Emerging roles for lipids in non-apoptotic cell death. Cell Death Differ. 23, 1099–1109 (2016).
Hassannia, B., Vandenabeele, P. & Vanden Berghe, T. Targeting ferroptosis to iron out cancer. Cancer Cell 35, 830–849 (2019).
Anasagasti, M. J. et al. Glutathione protects metastatic melanoma cells against oxidative stress in the murine hepatic microvasculature. Hepatology 27, 1249–1256 (1998).
Carretero, J. et al. Growth-associated changes in glutathione content correlate with liver metastatic activity of B16 melanoma cells. Clin. Exp. Metastasis 17, 567–574 (1999).
Huang, Z. Z. et al. Mechanism and significance of increased glutathione level in human hepatocellular carcinoma and liver regeneration. FASEB J. 15, 19–21 (2001).
Sayin, V. I. et al. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. eLife 6, e28083 (2017).
Chen, R. S. et al. Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway. Oncogene 28, 599–609 (2009).
Sato, M. et al. Loss of the cystine/glutamate antiporter in melanoma abrogates tumor metastasis and markedly increases survival rates of mice. Int. J. Cancer 147, 3224–3235 (2020).
Wang, X. et al. Mitochondrial calcium uniporter drives metastasis and confers a targetable cystine dependency in pancreatic cancer. Cancer Res. 82, 2254–2268 (2022).
Cramer, S. L. et al. Systemic depletion of l-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat. Med. 23, 120–127 (2017).
Beatty, A. et al. Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1. Nat. Commun. 12, 2244 (2021).
Magtanong, L. et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol. 26, 420–432 (2019).
Xie, X. et al. BACH1-induced ferroptosis drives lymphatic metastasis by repressing the biosynthesis of monounsaturated fatty acids. Cell Death Dis. 14, 48 (2023).
D’Herde, K. & Krysko, D. V. Ferroptosis: oxidized PEs trigger death. Nat. Chem. Biol. 13, 4–5 (2017).
Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91–98 (2017).
Li, H. et al. The landscape of cancer cell line metabolism. Nat. Med. 25, 850–860 (2019).
Luis, G. et al. Tumor resistance to ferroptosis driven by stearoyl-CoA desaturase-1 (SCD1) in cancer cells and fatty acid biding protein-4 (FABP4) in tumor microenvironment promote tumor recurrence. Redox Biol. 43, 102006 (2021).
Tesfay, L. et al. Stearoyl-CoA desaturase 1 protects ovarian cancer cells from ferroptotic cell death. Cancer Res. 79, 5355–5366 (2019).
Liao, C. et al. Trichothecin inhibits invasion and metastasis of colon carcinoma associating with SCD-1-mediated metabolite alteration. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1865, 158540 (2020).
Friedmann Angeli, J. P. & Conrad, M. Selenium and GPX4, a vital symbiosis. Free Radic. Biol. Med. 127, 153–159 (2018).
Moosmann, B. & Behl, C. Selenoproteins, cholesterol-lowering drugs, and the consequences: revisiting of the mevalonate pathway. Trends Cardiovasc. Med. 14, 273–281 (2004).
Shimada, K. et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat. Chem. Biol. 12, 497–503 (2016).
Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017).
Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).
Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019).
Garcia-Bermudez, J. et al. Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 567, 118–122 (2019).
Liu, W. et al. Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer. Nat. Commun. 12, 5103 (2021).
Oweira, H. et al. Prognostic value of site-specific metastases in pancreatic adenocarcinoma: a surveillance epidemiology and end results database analysis. World J. Gastroenterol. 23, 1872–1880 (2017).
Flerin, N. C., Pinioti, S., Menga, A., Castegna, A. & Mazzone, M. Impact of immunometabolism on cancer metastasis: a focus on T cells and macrophages. Cold Spring Harb. Perspect. Med. 10, a037044 (2020).
Kayden, H. J., Karmen, A. & Dumont, A. Alterations in the fatty acid composition of human lymph and serum lipoproteins by single feedings. J. Clin. Invest. 42, 1373–1381 (1963).
Gracia, G., Cao, E., Johnston, A. P. R., Porter, C. J. H. & Trevaskis, N. L. Organ-specific lymphatics play distinct roles in regulating HDL trafficking and composition. Am. J. Physiol. Gastrointest. Liver Physiol. 318, G725–G735 (2020).
Nguyen, P. et al. Liver lipid metabolism. J. Anim. Physiol. Anim. Nutr. 92, 272–283 (2008).
Montero-Calle, A. et al. Metabolic reprogramming helps to define different metastatic tropisms in colorectal cancer. Front. Oncol. 12, 903033 (2022).
Veldhuizen, R., Nag, K., Orgeig, S. & Possmayer, F. The role of lipids in pulmonary surfactant. Biochim. Biophys. Acta 1408, 90–108 (1998).
Rinaldi, G. et al. In vivo evidence for serine biosynthesis-defined sensitivity of lung metastasis, but not of primary breast tumors, to mTORC1 inhibition. Mol. Cell 81, 386–397 (2021).
Huang, Y. C. et al. Involvement of ACACA (acetyl-CoA carboxylase α) in the lung pre-metastatic niche formation in breast cancer by senescence phenotypic conversion in fibroblasts. Cell. Oncol. 46, 643–660 (2023).
Cordero, A. et al. FABP7 is a key metabolic regulator in HER2+ breast cancer brain metastasis. Oncogene 38, 6445–6460 (2019).
Zou, Y. et al. Polyunsaturated fatty acids from astrocytes activate PPARγ signaling in cancer cells to promote brain metastasis. Cancer Discov. 9, 1720–1735 (2019).
Tiwary, S. et al. Metastatic brain tumors disrupt the blood–brain barrier and alter lipid metabolism by inhibiting expression of the endothelial cell fatty acid transporter Mfsd2a. Sci. Rep. 8, 8267 (2018).
Kim, J. & DeBerardinis, R. J. Mechanisms and implications of metabolic heterogeneity in cancer. Cell Metab. 30, 434–446 (2019).
Wang, D. & Dubois, R. N. Eicosanoids and cancer. Nat. Rev. Cancer 10, 181–193 (2010).
Schmitz, G. & Ecker, J. The opposing effects of n–3 and n–6 fatty acids. Prog. Lipid Res. 47, 147–155 (2008).
Castellone, M. D., Teramoto, H., Williams, B. O., Druey, K. M. & Gutkind, J. S. Prostaglandin E2 promotes colon cancer cell growth through a Gs–axin–β-catenin signaling axis. Science 310, 1504–1510 (2005).
Bottcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 (2018).
Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).
Bell, C. R. et al. Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations. Nat. Commun. 13, 2063 (2022).
Nikolos, F. et al. Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors. Nat. Commun. 13, 1487 (2022).
Yan, G. et al. A RIPK3–PGE2 circuit mediates myeloid-derived suppressor cell-potentiated colorectal carcinogenesis. Cancer Res. 78, 5586–5599 (2018).
Cen, B. et al. Prostaglandin E2 induces miR675-5p to promote colorectal tumor metastasis via modulation of p53 expression. Gastroenterology 158, 971–984 (2020).
Gong, Z. et al. Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment. Immunity 55, 1483–1500 (2022).
Zhang, Y. et al. Prostaglandin E2 receptor 4 mediates renal cell carcinoma intravasation and metastasis. Cancer Lett. 391, 50–58 (2017).
Elwakeel, E. et al. Disruption of prostaglandin E2 signaling in cancer-associated fibroblasts limits mammary carcinoma growth but promotes metastasis. Cancer Res. 82, 1380–1395 (2022).
Hamy, A. S. et al. Celecoxib with neoadjuvant chemotherapy for breast cancer might worsen outcomes differentially by COX-2 expression and ER status: exploratory analysis of the REMAGUS02 trial. J. Clin. Oncol. 37, 624–635 (2019).
Lucotti, S. et al. Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2. J. Clin. Invest. 129, 1845–1862 (2019).
Kim, J. et al. Suppression of prostate tumor cell growth by stromal cell prostaglandin D synthase-derived products. Cancer Res. 65, 6189–6198 (2005).
Zhang, B. et al. PGD2/PTGDR2 signaling restricts the self-renewal and tumorigenesis of gastric cancer. Stem Cells 36, 990–1003 (2018).
Mattoscio, D. et al. Resolvin D1 reduces cancer growth stimulating a protective neutrophil-dependent recruitment of anti-tumor monocytes. J. Exp. Clin. Cancer Res. 40, 129 (2021).
Penke, L. R. et al. FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis. J. Clin. Invest. 128, 2389–2405 (2018).
Sun, L. et al. Resolvin D1 prevents epithelial–mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP. J. Exp. Clin. Cancer Res. 38, 170 (2019).
Wu, F. et al. Prostaglandin E1 inhibits GLI2 amplification-associated activation of the Hedgehog pathway and drug refractory tumor growth. Cancer Res. 80, 2818–2832 (2020).
Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).
Gaude, E. & Frezza, C. Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival. Nat. Commun. 7, 13041 (2016).
Gatto, F., Schulze, A. & Nielsen, J. Systematic analysis reveals that cancer mutations converge on deregulated metabolism of arachidonate and xenobiotics. Cell Rep. 16, 878–895 (2016).
Li, P. et al. Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis. Nat. Immunol. 21, 1444–1455 (2020).
Tousignant, K. D. et al. Lipid uptake is an androgen-enhanced lipid supply pathway associated with prostate cancer disease progression and bone metastasis. Mol. Cancer Res. 17, 1166–1179 (2019).
Glatz, J. F. C., Wang, F., Nabben, M. & Luiken, J. CD36 as a target for metabolic modulation therapy in cardiac disease. Expert Opin. Ther. Targets 25, 393–400 (2021).
Ma, X. et al. CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab. 33, 1001–1012 (2021).
Aloia, A. et al. A fatty acid oxidation-dependent metabolic shift regulates the adaptation of BRAF-mutated melanoma to MAPK inhibitors. Clin. Cancer Res. 25, 6852–6867 (2019).
Holubarsch, C. J. et al. A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study. Clin. Sci. 113, 205–212 (2007).
Parik, S. et al. GBM tumors are heterogeneous in their fatty acid metabolism and modulating fatty acid metabolism sensitizes cancer cells derived from recurring GBM tumors to temozolomide. Front. Oncol. 12, 988872 (2022).
Lien, E. C. et al. Low glycaemic diets alter lipid metabolism to influence tumour growth. Nature 599, 302–307 (2021).
Hangauer, M. J. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551, 247–250 (2017).
Wang, W. et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019).
Rodriguez, R., Schreiber, S. L. & Conrad, M. Persister cancer cells: iron addiction and vulnerability to ferroptosis. Mol. Cell 82, 728–740 (2022).
Tsoi, J. et al. Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress. Cancer Cell 33, 890–904 (2018).
Matsushita, M. et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J. Exp. Med. 212, 555–568 (2015).
Matin-Perez, M., Uxue, U. U., Bigas, C. & Benitah, S. A. Lipid metabolism in metastasis and therapy. Curr. Opin. Syst. Biol. 28, 100401 (2021).
Lignitto, L. et al. Nrf2 activation promotes lung cancer metastasis by inhibiting the degradation of Bach1. Cell 178, 316–329 (2019).
Wiel, C. et al. BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell 178, 330–345 (2019).
Lien, E. C. & Vander Heiden, M. G. A framework for examining how diet impacts tumour metabolism. Nat. Rev. Cancer 19, 651–661 (2019).
Li, Z., Seehawer, M. & Polyak, K. Untangling the web of intratumour heterogeneity. Nat. Cell Biol. 24, 1192–1201 (2022).
Zou, Y. et al. Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 585, 603–608 (2020).
Posor, Y., Jang, W. & Haucke, V. Phosphoinositides as membrane organizers. Nat. Rev. Mol. Cell Biol. 23, 797–816 (2022).
Bailey, A. P. et al. Antioxidant role for lipid droplets in a stem cell niche of Drosophila. Cell 163, 340–353 (2015).
Qiu, Z. et al. GBA1-dependent membrane glucosylceramide reprogramming promotes liver cancer metastasis via activation of the Wnt/β-catenin signalling pathway. Cell Death Dis. 13, 508 (2022).
Kurtova, A. V. et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature 517, 209–213 (2015).
Carter, B. Z. et al. An ARC-regulated IL1β/Cox-2/PGE2/β-catenin/ARC circuit controls leukemia–microenvironment interactions and confers drug resistance in AML. Cancer Res. 79, 1165–1177 (2019).
Acknowledgements
We thank all members of the Division of Metabolism and Microenvironment for helpful discussions. This work was supported by funding from the German Research Foundation (SCHU2670-2 and SPP2306). A.B.C.-F. is funded by a fellowship from the São Paulo Research Foundation (FAPESP).
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Vogel, F.C.E., Chaves-Filho, A.B. & Schulze, A. Lipids as mediators of cancer progression and metastasis. Nat Cancer 5, 16–29 (2024). https://doi.org/10.1038/s43018-023-00702-z
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DOI: https://doi.org/10.1038/s43018-023-00702-z
