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Deciphering Brain Metastasis Stem Cell Properties From Colorectal Cancer Highlights Specific Stemness Signature and Shared Molecular Features
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Edité par CCSD ; Philadelphia, PA : American Gastroenterological Association, [2015]- -
International audience. BACKGROUND & AIMS: Brain metastases (BMs) from colorectalcancer (CRC) are associated with significant morbidityand mortality, with chemoresistance and short overall survival.Migrating cancer stem cells with the ability to initiate BM havebeen described in breast and lung cancers. In this study, wedescribe the identification and characterization of cancer stemcells in BM from CRC.METHODS: Four brain metastasis stem cell lines from patientswith colorectal cancer (BM-SC-CRC1 to BM-SC-CRC4) wereobtained by mechanical dissociation of patient’s tumors andselection of cancer stem cells by appropriate culture conditions.BM-SC-CRCs were characterized in vitro by clonogenic andlimiting-dilution assays, as well as immunofluorescence andWestern blot analyses. In ovo, a chicken chorioallantoic membrane(CAM) model and in vivo, xenograft experiments usingBALB/c-nude mice were realized. Finally, a whole exome andRNA sequencing analyses were performed.RESULTS: BM-SC-CRC formed metaspheres and containedtumor-initiating cells with self-renewal properties. Theyexpressed stem cell surface markers (CD44v6, CD44, andEpCAM) in serum-free medium and CRC markers (CK19, CK20and CDX-2) in fetal bovine serum-enriched medium. The CAMmodel demonstrated their invasive and migratory capabilities.Moreover, mice intracranial xenotransplantation of BM-SCCRCsadequately recapitulated the original patient BM phenotype.Finally, transcriptomic and genomic approaches showed asignificant enrichment of invasiveness and specific stemnesssignatures and highlighted KMT2C as a potential candidategene to potentially identify high-risk CRC patients.CONCLUSIONS: This original study represents the first step inCRC BM initiation and progression comprehension, and furtherinvestigation could open the way to new therapeutics avenuesto improve patient prognosis.
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