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Galectin-3 depletion tames pro-tumoural microglia and restrains cancer cells growth
Alberto Rivera-Ramos1, Luis Cruz-Hernández1, Rocío Talaverón1
1Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen Del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Spain.
Abstract:
Galectin-3 (Gal-3) is a multifunctional protein that plays a pivotal role in the initiation and progression of various central nervous system diseases, including cancer. Although the involvement of Gal-3 in tumour progression, resistance to treatment and immunosuppression has long been studied in different cancer types, mainly outside the central nervous system, its elevated expression in myeloid and glial cells underscores its profound impact on the brain's immune response. In this context, microglia and infiltrating macrophages, the predominant non-cancerous cells within the tumour microenvironment, play critical roles in establishing an immunosuppressive milieu in diverse brain tumours. Through the utilisation of primary cell cultures and immortalised microglial cell lines, we have elucidated the central role of Gal-3 in promoting cancer cell migration, invasion, and an immunosuppressive microglial phenotypic activation. Furthermore, employing two distinct in vivo models encompassing primary (glioblastoma) and secondary brain tumours (breast cancer brain metastasis), our histological and transcriptomic analysis show that Gal-3 depletion triggers a robust pro-inflammatory response within the tumour microenvironment, notably based on interferon-related pathways. Interestingly, this response is prominently observed in tumour-associated microglia and macrophages (TAMs), resulting in the suppression of cancer cells growth.
Insights
Galectin-3 (Gal-3) drives brain tumor growth and immune suppression. Depleting Gal-3 activates anti-tumor immunity in microglia and macrophages, inhibiting cancer cell proliferation.
Area of Science:
- Neuroscience
- Immunology
- Oncology
Background:
- Galectin-3 (Gal-3) is implicated in central nervous system diseases and cancer progression.
- Elevated Gal-3 in brain myeloid and glial cells impacts immune response within the tumor microenvironment.
- Microglia and macrophages contribute to an immunosuppressive milieu in brain tumors.
Purpose of the Study:
- To investigate the role of Gal-3 in brain tumor progression and the immune microenvironment.
- To elucidate Gal-3's function in cancer cell migration, invasion, and microglial activation.
- To assess the impact of Gal-3 depletion on the anti-tumor immune response in vivo.
Main Methods:
- Primary cell cultures and immortalized microglial cell lines were used to study Gal-3's effects.
- In vivo experiments utilized models of primary glioblastoma and secondary brain metastases.
- Histological and transcriptomic analyses were performed on Gal-3 depleted models.
Main Results:
- Gal-3 promotes cancer cell migration, invasion, and immunosuppressive microglial activation.
- Gal-3 depletion in vivo induced a pro-inflammatory response, particularly involving interferon pathways.
- This response was prominent in tumor-associated microglia and macrophages (TAMs), leading to suppressed tumor growth.
Conclusions:
- Gal-3 is a key mediator of immune suppression and tumor progression in brain cancers.
- Targeting Gal-3 can reprogram TAMs towards a pro-inflammatory, anti-tumor phenotype.
- Gal-3 inhibition represents a potential therapeutic strategy for brain tumors.
