Harbeck, N. et al. Breast cancer. Nat. Rev. Dis. Primers 5, 66 (2019).
Chen, W., Hoffmann, A. D., Liu, H. & Liu, X. Organotropism: new insights into molecular mechanisms of breast cancer metastasis. NPJ Precis. Oncol. 2, 4 (2018).
Achrol, A. S. et al. Brain metastases. Nat. Rev. Dis. Primers 5, 5 (2019).
Cancer Genome Atlas Network Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).
Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).
Liu, Y. et al. Deletions linked to TP53 loss drive cancer through p53-independent mechanisms. Nature 531, 471–475 (2016).
Ferraro, G. B. et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nat. Cancer 2, 414–428 (2021).
Lorger, M. Tumor microenvironment in the brain. Cancers (Basel) 4, 218–243 (2012).
Adler, O. et al. Reciprocal interactions between innate immune cells and astrocytes facilitate neuroinflammation and brain metastasis via lipocalin-2. Nat. Cancer 4, 401–418 (2023).
Schwartz, H. et al. Incipient melanoma brain metastases instigate astrogliosis and neuroinflammation. Cancer Res. 76, 4359–4371 (2016).
Priego, N. et al. STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis article. Nat. Med. 24, 1024–1035 (2018).
Doron, H. et al. Inflammatory activation of astrocytes facilitates melanoma brain tropism via the CXCL10-CXCR3 signaling axis. Cell Rep. 28, 1785–1798 (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).
Jin, X. et al. A metastasis map of human cancer cell lines. Nature 588, 331–336 (2020).
Aaltonen, L. A. et al. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020).
Razavi, P. et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell 34, 427–438 (2018).
Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017).
Pereira, B. et al. The somatic mutation profiles of 2,433 breast cancers refine their genomic and transcriptomic landscapes. Nat. Commun. 7, 11479 (2016).
Nguyen, B. et al. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell 185, 563–575 (2022).
De Mattos-Arruda, L. et al. The genomic and immune landscapes of lethal metastatic breast cancer. Cell Rep. 27, 2690–2708 (2019).
Schrijver, W. A. M. E. et al. Mutation profiling of key cancer genes in primary breast cancers and their distant metastases. Cancer Res. 78, 3112–3121 (2018).
Siegel, M. B. et al. Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer. J. Clin. Invest. 128, 1371–1383 (2018).
Saunus, J. M. et al. Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance. J. Pathol. 237, 363–378 (2015).
Ding, L. et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999–1005 (2010).
Piccirilli, C. et al. Allelic deletions on chromosome-17 and mutations in the p53 gene in tumors metastatic to brain. Int. J. Oncol. 4, 37–42 (1994).
Wang, Z. et al. Loss-of-function but not gain-of-function properties of mutant TP53 are critical for the proliferation, survival and metastasis of a broad range of cancer cells. Cancer Discov. 14, 362–379 (2024).
Xu, J. et al. 14-3-3ζ turns TGF-β’s function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2. Cancer Cell 27, 177–192 (2015).
Zhang, X. H.-F. et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16, 67–78 (2009).
Jain, E. The Metastatic Breast Cancer Project: leveraging patient-partnered research to expand the clinical and genomic landscape of metastatic breast cancer and accelerate discoveries. Preprint at medRxiv https://doi.org/10.1101/2023.06.07.23291117 (2023).
Parry, M. Introducing the Metastatic Breast Cancer Project: a novel patient-partnered initiative to accelerate understanding of MBC. ESMO Open 3, e000452 (2018).
Riihimäki, M., Thomsen, H., Sundquist, K., Sundquist, J. & Hemminki, K. Clinical landscape of cancer metastases. Cancer Med. 7, 5534–5542 (2018).
Cancer Genome Atlas Research Network Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
Xiong, Z., Gharagozlou, S., Vengco, I., Chen, W. & Ohlfest, J. R. Effective CpG immunotherapy of breast carcinoma prevents but fails to eradicate established brain metastasis. Clin. Cancer Res. 14, 5484–5493 (2008).
Rockwell, S. C., Kallman, R. F. & Fajardo, L. F. Characteristics of a serially transplanted mouse mammary tumor and its tissue-culture-adapted derivative. J. Natl Cancer Inst. 49, 735–749 (1972).
Gioanni, J. et al. Establishment and characterisation of a new tumorigenic cell line with a normal karyotype derived from a human breast adenocarcinoma. Br. J. Cancer 62, 8–13 (1990).
Redman-Rivera, L. N. et al. Acquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes. Nat. Commun. 12, 5184 (2021).
Quail, D. F. & Joyce, J. A. The microenvironmental landscape of brain tumors. Cancer Cell 31, 326–341 (2017).
Savino, A. M. et al. Metabolic adaptation of acute lymphoblastic leukemia to the central nervous system microenvironment depends on stearoyl-CoA desaturase. Nat. Cancer 1, 998–1009 (2020).
Schild, T., Low, V., Blenis, J. & Gomes, A. P. Unique metabolic adaptations dictate distal organ-specific metastatic colonization. Cancer Cell 33, 347–354 (2018).
Perelroizen, R. et al. Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity. Brain 145, 3288–3307 (2022).
Elahi, L. S. et al. Valproic acid targets IDH1 mutants through alteration of lipid metabolism. NPJ Metab. Health Dis. 2, 20 (2024).
Ferris, H. A. et al. Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc. Natl Acad. Sci. USA 114, 1189–1194 (2017).
Moore, S. A. Polyunsaturated fatty acid synthesis and release. J. Mol. Neurosci. 16, 195–200 (2001).
Medina, J. M. & Tabernero, A. Astrocyte-synthesized oleic acid behaves as a neurotrophic factor for neurons. J. Physiol. Paris 96, 265–271 (2002).
Bernoud, N. et al. Astrocytes are mainly responsible for the polyunsaturated fatty acid enrichment in blood–brain barrier endothelial cells in vitro. J. Lipid Res. 39, 1816–1824 (1998).
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).
Koundouros, N. & Poulogiannis, G. Reprogramming of fatty acid metabolism in cancer. Br. J. Cancer 122, 4–22 (2020).
Guthmann, F., Haupt, R., Looman, A. C., Spener, F. & Rüstow, B. Fatty acid translocase/CD36 mediates the uptake of palmitate by type II pneumocytes. Am. J. Physiol. 277, L191–L196 (1999).
Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41–45 (2017).
Vallvé, J.-C. et al. Unsaturated fatty acids and their oxidation products stimulate CD36 gene expression in human macrophages. Atherosclerosis 164, 45–56 (2002).
Yang, P. et al. Dietary oleic acid-induced CD36 promotes cervical cancer cell growth and metastasis via up-regulation Src/ERK pathway. Cancer Lett. 438, 76–85 (2018).
Feng, W. W., Zuppe, H. T. & Kurokawa, M. The role of CD36 in cancer progression and its value as a therapeutic target. Cells 12, 1605 (2023).
Röhrig, F. & Schulze, A. The multifaceted roles of fatty acid synthesis in cancer. Nat. Rev. Cancer 16, 732–749 (2016).
Sen, U., Coleman, C. & Sen, T. Stearoyl coenzyme A desaturase-1: multitasker in cancer, metabolism, and ferroptosis. Trends Cancer 9, 480–489 (2023).
Li, H. et al. The landscape of cancer cell line metabolism. Nat. Med. 25, 850–860 (2019).
Kaya-Okur, H. S., Janssens, D. H., Henikoff, J. G., Ahmad, K. & Henikoff, S. Efficient low-cost chromatin profiling with CUT&Tag. Nat. Protoc. 15, 3264–3283 (2020).
Kirschner, K. et al. Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53. PLoS Genet. 11, e1005053 (2015).
Mirza, A. et al. Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression. Oncogene 22, 3645–3654 (2003).
Bené, H., Lasky, D. & Ntambi, J. M. Cloning and characterization of the human stearoyl-CoA desaturase gene promoter: transcriptional activation by sterol regulatory element binding protein and repression by polyunsaturated fatty acids and cholesterol. Biochem. Biophys. Res. Commun. 284, 1194–1198 (2001).
Girardini, J. E. et al. A Pin1/mutant p53 axis promotes aggressiveness in breast cancer. Cancer Cell 20, 79–91 (2011).
Zhao, H. et al. High expression of DEPDC1 promotes malignant phenotypes of breast cancer cells and predicts poor prognosis in patients with breast cancer. Front. Oncol. 9, 262 (2019).
Brigandi, R. A., Zhu, J., Murnane, A. A., Reedy, B. A. & Shakib, S. A phase 1 randomized, placebo-controlled trial with a topical inhibitor of stearoyl-coenzyme A desaturase 1 under occluded and nonoccluded conditions. Clin. Pharmacol. Drug Dev. 8, 270–280 (2019).
Menendez, J. A. & Lupu, R. Fatty acid synthase (FASN) as a therapeutic target in breast cancer. Expert Opin. Ther. Targets 21, 1001–1016 (2017).
Tracz-Gaszewska, Z. & Dobrzyn, P. Stearoyl-CoA desaturase 1 as a therapeutic target for the treatment of cancer. Cancers (Basel) 11, 948 (2019).
Cheng, Y.-J., Fan, F., Zhang, Z. & Zhang, H. Lipid metabolism in malignant tumor brain metastasis: reprogramming and therapeutic potential. Expert Opin. Ther Targets 27, 861–878 (2023).
Tsherniak, A. et al. Defining a cancer dependency map. Cell 170, 564–576 (2017).
Sivanand, S. et al. Cancer tissue of origin constrains the growth and metabolism of metastases. Nat. Metab. 9, 1668–1681 (2024).
Ramaswamy, S., Ross, K. N., Lander, E. S. & Golub, T. R. A molecular signature of metastasis in primary solid tumors. Nat. Genet. 33, 49–54 (2003).
Sanghvi, N. et al. Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues. Sci. Adv. 10, eadn0220 (2024).
Sammarco, A. et al. Targeting SCD triggers lipotoxicity of cancer cells and enhances anti-tumor immunity in breast cancer brain metastasis mouse models. Commun. Biol. 8, 562 (2025).
Zou, Z., Ohta, T. & Oki, S. ChIP-Atlas 3.0: a data-mining suite to explore chromosome architecture together with large-scale regulome data. Nucleic Acids Res. 52, W45–W53 (2024).
Zou, Z., Ohta, T., Miura, F. & Oki, S. ChIP-Atlas 2021 update: a data-mining suite for exploring epigenomic landscapes by fully integrating ChIP-seq, ATAC-seq and Bisulfite-seq data. Nucleic Acids Res. 50, W175–W182 (2022).
Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).
Zhang, X. H.-F. et al. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell 154, 1060–1073 (2013).
Duchnowska, R. et al. Brain metastasis prediction by transcriptomic profiling in triple-negative breast cancer. Clin. Breast Cancer 17, e65–e75 (2017).
Iwamoto, T. et al. Distinct gene expression profiles between primary breast cancers and brain metastases from pair-matched samples. Sci. Rep. 9, 13343 (2019).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
Reich, M. et al. GenePattern 2.0. Nat. Genet. 38, 500–501 (2006).
Smid, M. et al. Subtypes of breast cancer show preferential site of relapse. Cancer Res. 68, 3108–3114 (2008).
Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).
Van Neerven, S. et al. Inflammatory cytokine release of astrocytes in vitro is reduced by all-trans retinoic acid. J. Neuroimmunol. 229, 169–179 (2010).
Agnese, S. T., Spierto, F. W. & Hannon, W. H. Evaluation of four reagents for delipidation of serum. Clin. Biochem. 2, 98–100 (1983).
Segal, E. et al. Targeting angiogenesis-dependent calcified neoplasms using combined polymer therapeutics. PLoS ONE 4, e5233 (2009).
Sanjana, N. E., Shalem, O. & Zhang, F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783–784 (2014).
Shalem, O. et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84–87 (2014).
Wang, B. et al. ATXN1L, CIC, and ETS transcription factors modulate sensitivity to MAPK pathway inhibition. Cell Rep. 18, 1543–1557 (2017).
Doench, J. G. et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR–Cas9. Nat. Biotechnol. 34, 184–191 (2016).
Tanaka, A., To, J., O’Brien, B., Donnelly, S. & Lund, M. Selection of reliable reference genes for the normalisation of gene expression levels following time course LPS stimulation of murine bone marrow derived macrophages. BMC Immunol. 18, 43 (2017).
Pozzi, S. et al. MCP-1/CCR2 axis inhibition sensitizes the brain microenvironment against melanoma brain metastasis progression. JCI Insight 7, e154804 (2022).
Folch, J., Lees, M. & Sloane Stanley, G. H. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226, 497–509 (1957).
Leikin-Frenkel, A. et al. Dietary α linolenic acid in pregnant mice and during weaning increases brain docosahexaenoic acid and improves recognition memory in the offspring. J. Nutr. Biochem. 91, 108597 (2021).
Leikin-Frenkel, A. et al. The effect of α-linolenic acid enrichment in perinatal diets in preventing high fat diet-induced SCD1 increased activity and lipid disarray in adult offspring of low density lipoprotein receptor knockout (LDLRKO) mice. Prostaglandins Leukot. Essent. Fatty Acids 184, 102475 (2022).
Malitsky, S. et al. Viral infection of the marine alga Emiliania huxleyi triggers lipidome remodeling and induces the production of highly saturated triacylglycerol. New Phytol. 210, 88–96 (2016).
Zheng, L. et al. Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat. Commun. 6, 6001 (2015).
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).
Zhang, Y. et al. Model-based Analysis of ChIP–Seq (MACS). Genome Biol. 9, R137 (2008).
RamÃrez, F. et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 44, W160–W165 (2016).
Stuart, T., Srivastava, A., Madad, S., Lareau, C. A. & Satija, R. Single-cell chromatin state analysis with Signac. Nat. Methods 18, 1333–1341 (2021).
Zerbib, J. et al. Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage. Nat. Commun. 15, 7772 (2024).
Theodoropoulos, P. C. et al. Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase. Nat. Chem. Biol. 12, 218–225 (2016).
Zhu, L. et al. A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis. EMBO Mol. Med. 14, e14552 (2022).
Iorio, F. et al. A landscape of pharmacogenomic interactions in cancer. Cell 166, 740–754 (2016).