Single-cell profiling and zebrafish avatars reveal LGALS1 as immunomodulating target in glioblastoma.

Abstract

Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM-associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient-derived GBM stem cell cultures and combined single-cell RNA sequencing of GAM-GBM co-cultures and real-time in vivo monitoring of GAM-GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM-induced GAM polarization and the ability to attract and activate GAMs-features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock-out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM-GBM interactions can be studied in a clinically relevant way using co-cultures and avatar models, while offering new opportunities to identify promising immune-modulating targets.

• Authors: Lise Finotto, Basiel Cole, Wolfgang Giese, Elisabeth Baumann, Annelies Claeys, Maxime Vanmechelen, Brecht Decraene, Marleen Derweduwe, Nikolina Dubroja Lakic, Gautam Shankar, Madhu Nagathihalli Kantharaju, Jan Philipp Albrecht, Ilse Geudens, Fabio Stanchi, Keith L Ligon, Bram Boeckx, Diether Lambrechts, Kyle Harrington, Ludo Van Den Bosch, Steven De Vleeschouwer, Frederik De Smet, Holger Gerhardt
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 15 Issue 11 Pg. e18144 (11 08 2023) ISSN: 1757-4684 [Electronic] England
• PMID: 37791581 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2023 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Galectin 1
• LGALS1 protein, human

Topics

• Animals
• Humans
• Glioblastoma (pathology)
• Zebrafish
• Galectin 1 (genetics, metabolism, therapeutic use)
• Cell Line, Tumor
• Macrophages (metabolism)
• Brain Neoplasms (pathology)
• Tumor Microenvironment (genetics)