Identifying specific targets to control macrophage infiltration of tumors
PhD thesis committee
- Dr. Hélène Moreau – Rapporteur – Institut Curie, Paris
- Dr. Guillaume Montagnac – Rapporteur – Institut Gustave Roussy, Paris
- Dr. Olivier Destaing – Rapporteur – Institut pour l’avancée des biosciences centre de recherche UGA, Grenoble
- Pr. Christel Lutz – Examiner - Institut de Pharmacologie et de Biologie Structurale
- Dr. Véronique Le Cabec – PhD supervisor – Institut de Pharmacologie et de Biologie Structurale
- Dr. Frédéric Lagarrigue – PhD co-supervisor - Institut de Pharmacologie et de Biologie Structurale
- Dr. Arnaud Labrousse – Tutor - Institut de Pharmacologie et de Biologie Structurale
Macrophages are innate immune cells capable of infiltrating all tissues of the body. In the case of solid cancers, macrophages are massively recruited into the tumour. Their abundance in the tumour microenvironment is a factor of poor prognosis because they promote tumour growth, neo-angiogenesis, chemoresistance and the development of metastases. Therefore, controlling macrophage infiltration in tumours is a therapeutic challenge. Previous studies have revealed that macrophages adapt their mode of migration to the physical properties of the extracellular matrix. Like other leukocytes, they use the amoeboid mode of migration to infiltrate soft or inflamed tissues. In sharp contrast, they use mesenchymal migration to infiltrate dense tumours in an integrin-dependent manner. To date, there are no specific inhibitors of mesenchymal migration.
- Here, we developed and performed a pan-genomic CRISPR/Cas9 screen to identify the molecular players in mesenchymal migration. This screen enabled us to identify 94 potential effectors of this migration mode. Among these effectors, we identified regulators of integrin activity and were able to demonstrate the signalling pathway used by macrophages to regulate their activity during migration.
- This work opens the way to identifying relevant targets for specifically blocking TAM recruitment while maintaining an effective immune response.