Deciphering Brain Metastasis Stem Cell Properties From Colorectal Cancer Highlights Specific Stemness Signature and Shared Molecular Features
Résumé
BACKGROUND & AIMS: Brain metastases (BMs) from colorectal
cancer (CRC) are associated with significant morbidity
and mortality, with chemoresistance and short overall survival.
Migrating cancer stem cells with the ability to initiate BM have
been described in breast and lung cancers. In this study, we
describe the identification and characterization of cancer stem
cells in BM from CRC.
METHODS: Four brain metastasis stem cell lines from patients
with colorectal cancer (BM-SC-CRC1 to BM-SC-CRC4) were
obtained by mechanical dissociation of patient’s tumors and
selection of cancer stem cells by appropriate culture conditions.
BM-SC-CRCs were characterized in vitro by clonogenic and
limiting-dilution assays, as well as immunofluorescence and
Western blot analyses. In ovo, a chicken chorioallantoic membrane
(CAM) model and in vivo, xenograft experiments using
BALB/c-nude mice were realized. Finally, a whole exome and
RNA sequencing analyses were performed.
RESULTS: BM-SC-CRC formed metaspheres and contained
tumor-initiating cells with self-renewal properties. They
expressed stem cell surface markers (CD44v6, CD44, and
EpCAM) in serum-free medium and CRC markers (CK19, CK20
and CDX-2) in fetal bovine serum-enriched medium. The CAM
model demonstrated their invasive and migratory capabilities.
Moreover, mice intracranial xenotransplantation of BM-SCCRCs
adequately recapitulated the original patient BM phenotype.
Finally, transcriptomic and genomic approaches showed a
significant enrichment of invasiveness and specific stemness
signatures and highlighted KMT2C as a potential candidate
gene to potentially identify high-risk CRC patients.
CONCLUSIONS: This original study represents the first step in
CRC BM initiation and progression comprehension, and further
investigation could open the way to new therapeutics avenues
to improve patient prognosis.
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