Tumor cell E-selectin ligands determine partialefficacy of bortezomib on spontaneous lung metastasis formation of solid human tumors in vivo

Tobias Lange, Ursula Valentiner, Daniel Wicklein, Hanna Maar, Vera Labitzky, Ann-Kristin Ahlers, Sarah Starzonek, Sandra Genduso, Lisa Staffeldt, Carolin Pahlow, Anna-Maria Dück, Christine Stürken, Anke Baranowsky, Alexander T Bauer, Etmar Bulk, Albrecht Schwab, Kristoffer Riecken, Christian Börnchen, Rainer Kiefmann, Valsamma AbrahamHorace M DeLisser, Timo Gemoll, Jens K Habermann, Andreas Block, Klaus Pantel, Udo Schumacher

Abstract

Extravasation of circulating tumor cells (CTCs) is critical for metastasis and is initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here, we show that the clinically approved proteasome inhibitor bortezomib (BZM; Velcade) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns. The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohistochemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and thus distant metastasis formation in malignancies expressing low-affinity E-selectin ligands.

Original languageEnglish
JournalMolecular Therapy
Volume30
Issue number4
Pages (from-to)1536-1552
Number of pages17
ISSN1525-0016
DOIs
Publication statusPublished - 06.04.2022

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