{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:45:32Z","timestamp":1790635532989,"version":"4.1.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004375","name":"Tel Aviv University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004375","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Exp Metastasis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Colorectal cancer (CRC) is a leading cause of cancer-related mortality in the Western world. While brain metastasis (BMs) are relatively uncommon in CRC, they represent the fourth most frequent cause of BMs overall, and their occurrence is increasingly recognized as a complication in advanced CRC, associated with poor prognosis and limited treatment options.\u00a0The brain microenvironment presents unique metabolic challenges, including low oxygen levels and restricted lipid availability. In order to survive in this hostile environment, CRC cells must acquire metabolic adaptations allowing them to survive and proliferate. To identify key drivers that enable CRC cells to metastasize to and survive within the brain, we conducted a transcriptomic screen of CRC BMs and compared it to liver metastasis (LMs). FOXM1, a transcription factor critical for tumor progression, was identified among the upregulated genes, and these results were validated by immunohistochemistry. To study the role of the brain microenvironment in mediating FOXM1 expression, we examined FOXM1 expression in CRC cell lines grown in either astrocyte-conditioned media (A-CM) or hepatocyte-conditioned media (H-CM). We observed a marked upregulation of FOXM1 following exposure to A-CM. Moreover, using an intracranial CRC BMs mouse model, a significant FOXM1 overexpression was observed. In accordance with the importance of fatty acid metabolism in BMs, our study revealed a significant correlation between FOXM1 and fatty acid synthase (FASN) in the CRC BMs, in agreement with public databases. These findings suggest that FOXM1 plays a key role in CRC BMs progression and may serve as a promising therapeutic target in this challenging disease setting.<\/jats:p>","DOI":"10.1007\/s10585-026-10397-y","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T02:09:29Z","timestamp":1777255769000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["FOXM1 expression is induced by the brain microenvironment and supports CRC brain metastatic adaptation"],"prefix":"10.1007","volume":"43","author":[{"given":"Fayhaa","family":"Khair","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inbal","family":"Greenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivan","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Shapira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asia","family":"Zubkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam","family":"Shomron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Raz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ido","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tami","family":"Rubinek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"10397_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.869010","author":"J Li","year":"2022","unstructured":"Li J, Chen D, Shen M (2022) Tumor microenvironment shapes colorectal cancer progression, metastasis, and treatment responses. Front Med. https:\/\/doi.org\/10.3389\/fmed.2022.869010","journal-title":"Front Med"},{"key":"10397_CR2","unstructured":"Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available from: https:\/\/gco.iarc.fr\/today, accessed [29 09 2021]. International Agency for Research on Cancer."},{"key":"10397_CR3","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-016-2290-5","author":"TD Christensen","year":"2016","unstructured":"Christensen TD, Spindler KLG, Palshof JA, Nielsen DL (2016) Systematic review: brain metastases from colorectal cancer\u2014incidence and patient characteristics. BMC Cancer. https:\/\/doi.org\/10.1186\/s12885-016-2290-5","journal-title":"BMC Cancer"},{"key":"10397_CR4","doi-asserted-by":"publisher","DOI":"10.1038\/nm1469","author":"PS Steeg","year":"2006","unstructured":"Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. https:\/\/doi.org\/10.1038\/nm1469","journal-title":"Nat Med"},{"key":"10397_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2016.12.001","author":"FJ Lowery","year":"2017","unstructured":"Lowery FJ, Yu D (2017) Brain metastasis: unique challenges and open opportunities. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. https:\/\/doi.org\/10.1016\/j.bbcan.2016.12.001","journal-title":"Biochimica et Biophysica Acta (BBA) - Reviews on Cancer"},{"key":"10397_CR6","doi-asserted-by":"publisher","unstructured":"Cox TR, Gartland A, Erler JT. The pre-metastatic niche: is metastasis random? Bonekey Rep. 2012;1(5). https:\/\/doi.org\/10.1038\/bonekey.2012.80","DOI":"10.1038\/bonekey.2012.80"},{"key":"10397_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1098","author":"IJ Fidler","year":"2003","unstructured":"Fidler IJ (2003) The pathogenesis of cancer metastasis: the \u201cseed and soil\u201d hypothesis revisited. Nat Rev Cancer. https:\/\/doi.org\/10.1038\/nrc1098","journal-title":"Nat Rev Cancer"},{"key":"10397_CR8","doi-asserted-by":"publisher","unstructured":"Malki A, Elruz RA, Gupta I, Allouch A, Vranic S, Al Moustafa AE. Molecular mechanisms of colon cancer progression and metastasis: Recent insights and advancements. Int J Mol Sci. 2021;22(1). https:\/\/doi.org\/10.3390\/ijms22010130","DOI":"10.3390\/ijms22010130"},{"key":"10397_CR9","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-022-01093-z","author":"R Wang","year":"2022","unstructured":"Wang R, Li J, Zhou X et al (2022) Single-cell genomic and transcriptomic landscapes of primary and metastatic colorectal cancer tumors. Genome Med. https:\/\/doi.org\/10.1186\/s13073-022-01093-z","journal-title":"Genome Med"},{"key":"10397_CR10","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2011.09.004","author":"CY Koo","year":"2012","unstructured":"Koo CY, Muir KW, Lam EWF (2012) FOXM1: from cancer initiation to progression and treatment. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. https:\/\/doi.org\/10.1016\/j.bbagrm.2011.09.004","journal-title":"Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms"},{"key":"10397_CR11","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-0640","author":"P Raychaudhuri","year":"2011","unstructured":"Raychaudhuri P, Park HJ (2011) FoxM1: a master regulator of tumor metastasis. Cancer Res. https:\/\/doi.org\/10.1158\/0008-5472.CAN-11-0640","journal-title":"Cancer Res"},{"key":"10397_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1217","author":"J Laoukili","year":"2005","unstructured":"Laoukili J, Kooistra MRH, Br\u00e1s A et al (2005) FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat Cell Biol. https:\/\/doi.org\/10.1038\/ncb1217","journal-title":"Nat Cell Biol"},{"key":"10397_CR13","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13348","author":"C Zhang","year":"2016","unstructured":"Zhang C, Wang Y, Feng YF et al (2016) Gli1 promotes colorectal cancer metastasis in a Foxm1-dependent manner by activating EMT and PI3k-AKT signaling. Oncotarget. https:\/\/doi.org\/10.18632\/oncotarget.13348","journal-title":"Oncotarget"},{"key":"10397_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01540-9","author":"X Li","year":"2023","unstructured":"Li X, Su W, Wu H et al (2023) FOXM1 maintains fatty acid homoeostasis through the SET7-H3K4me1-FASN axis. Cell Death Discov. https:\/\/doi.org\/10.1038\/s41420-023-01540-9","journal-title":"Cell Death Discov"},{"key":"10397_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2017.08.009","author":"D Nandi","year":"2018","unstructured":"Nandi D, Cheema PS, Jaiswal N, Nag A (2018) FoxM1: repurposing an oncogene as a biomarker. Semin Cancer Biol. https:\/\/doi.org\/10.1016\/j.semcancer.2017.08.009","journal-title":"Semin Cancer Biol"},{"key":"10397_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00183-y","author":"GB Ferraro","year":"2021","unstructured":"Ferraro GB, Ali A, Luengo A et al (2021) Fatty acid synthesis is required for breast cancer brain metastasis. Nat Cancer. https:\/\/doi.org\/10.1038\/s43018-021-00183-y","journal-title":"Nat Cancer"},{"key":"10397_CR17","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000030273","author":"W Li","year":"2022","unstructured":"Li W, Wang T, Zhu Y et al (2022) Brain metastasis from colorectal cancer: treatment, survival, and prognosis. Medicine. https:\/\/doi.org\/10.1097\/MD.0000000000030273","journal-title":"Medicine"},{"key":"10397_CR18","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.758681","author":"Q Chen","year":"2022","unstructured":"Chen Q, He L, Li Y et al (2022) Risk factors on the incidence and prognostic effects of colorectal cancer with brain metastasis: a SEER-based study. Front Oncol. https:\/\/doi.org\/10.3389\/fonc.2022.758681","journal-title":"Front Oncol"},{"key":"10397_CR19","doi-asserted-by":"publisher","DOI":"10.3816\/CCC.2009.n.016","author":"JP Mongan","year":"2009","unstructured":"Mongan JP, Fadul CE, Cole BF et al (2009) Brain metastasis from colorectal cancer: risk factors, incidence, and the possible role of chemokines. Clin Colorectal Cancer. https:\/\/doi.org\/10.3816\/CCC.2009.n.016","journal-title":"Clin Colorectal Cancer"},{"key":"10397_CR20","doi-asserted-by":"publisher","DOI":"10.3390\/ijms131215784","author":"YW Zang","year":"2012","unstructured":"Zang YW, Gu XD, Xiang JB, Chen ZY (2012) Brain metastases from colorectal cancer: microenvironment and molecular mechanisms. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms131215784","journal-title":"Int J Mol Sci"},{"key":"10397_CR21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0085448","author":"B Salhia","year":"2014","unstructured":"Salhia B, Kiefer J, Ross JTD et al (2014) Integrated genomic and epigenomic analysis of breast cancer brain metastasis. PLoS ONE. https:\/\/doi.org\/10.1371\/journal.pone.0085448","journal-title":"PLoS ONE"},{"key":"10397_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-18185-w","author":"JK Shim","year":"2022","unstructured":"Shim JK, Lim SH, Jeong JH et al (2022) A lignan from Alnus japonica inhibits glioblastoma tumorspheres by suppression of FOXM1. Sci Rep. https:\/\/doi.org\/10.1038\/s41598-022-18185-w","journal-title":"Sci Rep"},{"key":"10397_CR23","doi-asserted-by":"publisher","unstructured":"Zhang K, Zhu L, Fan M. Oxygen, a Key Factor Regulating Cell Behavior during Neurogenesis and Cerebral Diseases. Front Mol Neurosci. 2011;4. https:\/\/doi.org\/10.3389\/fnmol.2011.00005","DOI":"10.3389\/fnmol.2011.00005"},{"key":"10397_CR24","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.21996","author":"LM Xia","year":"2009","unstructured":"Xia LM, Huang WJ, Wang B et al (2009) Transcriptional up-regulation of FoxM1 in response to hypoxia is mediated by HIF-1. J Cell Biochem. https:\/\/doi.org\/10.1002\/jcb.21996","journal-title":"J Cell Biochem"},{"key":"10397_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.14","author":"J Cui","year":"2016","unstructured":"Cui J, Xia T, Xie D et al (2016) HGF\/Met and FOXM1 form a positive feedback loop and render pancreatic cancer cells resistance to Met inhibition and aggressive phenotypes. Oncogene. https:\/\/doi.org\/10.1038\/onc.2016.14","journal-title":"Oncogene"},{"key":"10397_CR26","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560","author":"S Chen","year":"2018","unstructured":"Chen S, Zhou Y, Chen Y, Gu J (2018) Fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. https:\/\/doi.org\/10.1093\/bioinformatics\/bty560","journal-title":"Bioinformatics"},{"key":"10397_CR27","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635","author":"A Dobin","year":"2013","unstructured":"Dobin A, Davis CA, Schlesinger F et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics. https:\/\/doi.org\/10.1093\/bioinformatics\/bts635","journal-title":"Bioinformatics"},{"key":"10397_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4197","author":"R Patro","year":"2017","unstructured":"Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C (2017) Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods. https:\/\/doi.org\/10.1038\/nmeth.4197","journal-title":"Nat Methods"},{"key":"10397_CR29","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw354","author":"P Ewels","year":"2016","unstructured":"Ewels P, Magnusson M, Lundin S, K\u00e4ller M (2016) MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics. https:\/\/doi.org\/10.1093\/bioinformatics\/btw354","journal-title":"Bioinformatics"},{"key":"10397_CR30","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. https:\/\/doi.org\/10.1186\/s13059-014-0550-8","journal-title":"Genome Biol"},{"key":"10397_CR31","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","author":"G Yu","year":"2012","unstructured":"Yu G, Wang LG, Han Y, He QY (2012) ClusterProfiler: an R package for comparing biological themes among gene clusters. OMICS J Integr Biol. https:\/\/doi.org\/10.1089\/omi.2011.0118","journal-title":"OMICS J Integr Biol"},{"key":"10397_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13000-014-0221-9","volume":"9","author":"N Fedchenko","year":"2014","unstructured":"Fedchenko N, Reifenrath J (2014) Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue\u2013a review. Diagn Pathol 9:1\u201312","journal-title":"Diagn Pathol"}],"container-title":["Clinical &amp; Experimental Metastasis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10585-026-10397-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10585-026-10397-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10585-026-10397-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:46:00Z","timestamp":1781649960000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10585-026-10397-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,27]]},"references-count":32,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["10397"],"URL":"https:\/\/doi.org\/10.1007\/s10585-026-10397-y","relation":{},"ISSN":["1573-7276"],"issn-type":[{"value":"1573-7276","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,27]]},"assertion":[{"value":"5 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Patient consent was waived by the Tel Aviv Sourasky Medical Center IRB due to the retrospective nature of the study and the use of anonymized FFPE samples.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"All procedures performed in studies involving human clinical samples were in accordance with written informed consent obtained from the research subjects by the Tel Aviv Sourasky Medical Center, under an approved institutional review board (IRB) (0137\u201321-TLV). The experiments on animals were conducted in accordance with institutional guidelines of the Sourasky Medical Center, and in accordance with current regulations and standards of the institutional Animal Care and Use Committee (approval 01-19-007).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Institutional review board statement"}}],"article-number":"22"}}