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Lgr5-negative cancer cells seed metastases in colorectal cancer

ABSTRACT: Cancer stem cells (CSCs) are a minority population of cancer cells that display stem cell-like multipotent and self-renewal properties. They give rise to the bulk of cancer cells with limited replicative potential. In colorectal cancer (CRC), CSCs are marked by expression of the leucine-rich repeat-containing G-protein receptor 5 (Lgr5). Since CSCs display multipotent and self-renewal properties, this population is thought to seed metastases. Here, we used a mouse model and human xenografts to investigate the cell-of-origin of metastases. Surprisingly, we found that most CRC cells that disseminated and entered the blood circulation were Lgr5-. Lgr5- cancer cells arriving at the metastatic site formed lesions in which Lgr5+ CSCs appeared. This plasticity could occur independently of stemness-inducing factors, and was an indispensable event for the outgrowth of metastases, since neutralization of this plasticity prevented metastatic outgrowth. Combined, our study shows that most metastases are seeded by Lgr5- cancer cells, and that these cells have a niche-independent and intrinsic capacity to become CSCs and restore epithelial hierarchy.

ORGANISM(S): Mus musculus

PROVIDER: GSE143988 | GEO | 2020/03/18

REPOSITORIES: GEO

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Project description:Among all cancers, colorectal cancer (CRC) is the 3rd most common and the 2nd leading cause of death worldwide. New therapeutic strategies are required to target cancer stem cells (CSCs), a subset of tumor cells highly resistant to present-day therapy and responsible for tumor relapse. CSCs display dynamic genetic and epigenetic alterations that allow quick adaptations to perturbations. Lysine-specific histone demethylase 1A (KDM1A), a FAD-dependent H3K4me1/2 and H3K9me1/2 demethylase, was found to be upregulated in several tumors and associated with a poor prognosis due to its ability to maintain CSCs staminal features. Here, we explored the potential role of KDM1A targeting in CRC by characterizing the effect of KDM1A silencing in differentiated and CRC stem cells (CRC-SCs). In CRC primary samples, KDM1A expression was associated with a worse prognosis, confirming its role as an independent negative prognostic factor of CRC. Consistently, biological assays such as methylcellulose colony formation, invasion, and migration assays demonstrated a significantly decreased self-renewal potential, as well as migration and invasion potential upon KDM1A silencing. Our untargeted omics approach (transcriptomic and proteomic) revealed the association of KDM1A silencing with CRC-SCs cytoskeletal and metabolism remodeling towards a differentiated phenotype (e.g., the activation of a collateral mitochondrial metabolic pathway independent from succinate-CoA ligase GDP-forming subunit beta 2, expressions of brush border’s protein villin, and ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2) suggesting a key role of KDM1A in cell metabolism. Also, KDM1A silencing resulted in a 3-fold increase in the expression of miR-506-3p. Lastly, loss of KDM1A markedly reduced 53BP1 DNA repair foci, implying the involvement of KDM1A in the DNA damage response. Overall, our results indicate that KDM1A plays a key role in CRC progression and therefore it represents a promising epigenetic target to prevent tumor relapse.

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Lgr5-negative cancer cells seed metastases in colorectal cancer

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