Single-cell profiling and zebrafish avatars reveal LGALS1 as immunomodulating target in glioblastoma
Authors
- L. Finotto
- B. Cole
- W. Giese
- E. Baumann
- A. Claeys
- M. Vanmechelen
- B. Decraene
- M. Derweduwe
- N. Dubroja Lakic
- G. Shankar
- M. Nagathihalli Kantharaju
- J.P. Albrecht
- I. Geudens
- F. Stanchi
- K.L. Ligon
- B. Boeckx
- D. Lambrechts
- K. Harrington
- L. Van Den Bosch
- S. De Vleeschouwer
- F. De Smet
- H. Gerhardt
Journal
- EMBO Molecular Medicine
Citation
- EMBO Mol Med 15 (11): e18144
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.