THE GALECTIN-1-GLYCAN AXIS PROMOTES DISSEMINATION AND METASTASIS OF BREAST CANCER

PERROTTA, RAMIRO; DALOTTO-MORENO, TOMÁS; MAHMOUD, YAMIL; CAGNONI, ALEJANDRO J.; PATACCINI, GABRIELA; LANARI, CLAUDIA; AGUIRRE-GHISO, JULIO ; MARIÑO, KARINA V.; RABINOVICH, GABRIEL A.; SALATINO, MARIANA

Virtual

Congreso; Reunion de Biociencias 2021; 2021

SAIC, SAI

The Galectin-1 (Gal1)/glycan axis controls several hallmarks of cancer. Here we investigated the role of Gal1 in breast cancer metastasis. We found at single cell level (scRNAseq) that Gal1 is synthesized by basal cell lineages and mammary stem cells (SCs) in normal mammary gland, where it promotes epithelial branching (**). Moreover, in the MMTV-NeuHER2/transgenic model, Gal1 was induced in early lesions (EL) compared to primary tumors (PT) (RNAseq). Addition of rGal1 to EL 3D-cultures promoted invasiveness (**) and increased epithelial-to- mesenchymal transition (EMT) markers (RT-PCR). This effect was confirmed in the aggressive Her2+ human cell line JIMT-1, which showed high levels of Gal1 (**, Western) and low levels of α2,6 sialyltransferase-1 (ST6Gal1), an enzyme that incorporates α2,6-linked sialic acid and blocks Gal1 binding (***, RT-PCR), compared with the HER2+ poorly metastatic cell line BT- 474. Accordingly, UPLC-HILIC/WAX revealed a Gal1-permissive glycan signature in JIMT1 (***). Treatment of JIMT-1 cells with rGal1, induced a CD44hi/CD24low cancer stem cell phenotype (***, flow cytometry) and enhanced migration (*), mamosphere formation (**) and EMT markers (RT-PCR). In vivo, treatment of HER2+PDX with rGal1 revealed increased lung metastasis (*). Bioinformatics analysis (TCGA) showed that tumors displaying a Gal- 1hi/ST6GAL1low phenotype had the poorest prognosis. Remarkably, these tumors upregulated transcripts associated with EMT and downregulated those linked to antitumor immunity (GSEA), as validated by the immunosuppressive infiltrate (Mixture). Our findings highlight the relevance of the Gal1/glycan axis in controlling normal mammary gland branching and emphasize its critical role in metastatic spreading of breast cancer. We propose that the Gal1/ST6Gal1 pair might serve as a possible biomarker capable of predicting the outcome of breast cancer patients and as a therapeutic target of novel anti-metastatic therapies (p