ENO2 drives tumor cell-induced M2 macrophage polarization to promote colorectal cancer liver metastasis
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Le résumé fourni par la source
Liver metastasis is the primary cause of mortality in colorectal cancer (CRC) patients. To decipher the underlying mechanisms, we performed single-cell RNA sequencing (scRNA-seq) on paired primary colorectal tumors, adjacent tissues and liver metastases from three CRC liver metastasis (CRLM) patients, alongside colorectal tumors and adjacent tissues from three non-metastatic CRC patients. Our analysis revealed a significant enrichment of Enolase 2-expressing (ENO2⁺) cancer cells in CRLM patients compared to their non-metastatic counterparts. Functional characterization, supported by bioinformatics and murine models, demonstrated that ENO2⁺ cancer cells exhibit enhanced epithelial-mesenchymal transition (EMT) and are critical drivers of CRLM. Mechanistically, the ENO2 protein directly binds to macrophage migration inhibitory factor (MIF) within cancer cells, stabilizing MIF by inhibiting its C-terminus of Hsc70-Interacting Protein (CHIP)-mediated ubiquitination and degradation. This ENO2-MIF interaction activates MIF signaling, fostering robust tumor cell-macrophage crosstalk that promotes M2 macrophage polarization, which is validated by spatial transcriptomics showing the colocalization of ENO2⁺ cancer cells and M2 macrophages. Crucially, both organoid and in vivo models confirmed that ENO2 in CRC cells is essential for inducing M2 macrophage polarization via the MIF pathway, thereby facilitating liver metastasis. Knockout of ENO2 significantly suppressed tumor growth and liver metastasis in mouse models. An inhibitor of the ENO2-MIF interaction, pyrithioxin, can effectively reduce the burden of liver metastasis in mice. Collectively, our findings identify ENO2 as a key driver of CRLM by stabilizing MIF to orchestrate M2 macrophage polarization, highlighting the ENO2-MIF axis as a promising therapeutic strategy for CRLM.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- ENO2 drives tumor cell-induced M2 macrophage polarization to promote colorectal cancer liver metastasis
- Date Crossref
- 05/05/2026
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Nanjing Medical University Department of General Surgery pays non établi dans la noticeUniversité ou école supérieure
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Sun Yat-sen University Department of Pathology pays non établi dans la noticeUniversité ou école supérieure
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Sun Yat-sen University Cancer Center pays non établi dans la noticeÉtablissement de santé
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Xuzhou Medical College pays non établi dans la noticeUniversité ou école supérieure
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Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine pays non établi dans la noticeStructure de recherche
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The Affiliated Shuyang Hospital of Xuzhou Medical University pays non établi dans la noticeUniversité ou école supérieure
Department of General Surgery — Nanjing Medical University, Department of Pathology — Sun Yat-sen University et Sun Yat-sen University Cancer Center, avec 3 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.