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Targeting integrin signaling in tumour-associated macrophages to combat cancer progression and resistance

Project description

Inhibition of tumour-associated macrophages as an anti-cancer treatment

Infiltration of tumour-associated macrophages (TAMs) is linked to poor cancer prognosis. Recent evidence indicates that inhibition of TAM migration reduces tumour infiltration and halts cancer progression in animal models. The EU-funded MacrophInt project proposes to target integrin signalling in TAMs as a new strategy to manipulate their infiltration into tumours. Integrins are central to the mesenchymal migratory mode of TAMs, which involves the adherence of cell podosomes to the surrounding extracellular matrix. Inhibition of TAM migration could be employed in conjunction with other anti-cancer strategies to improve patient clinical outcome.


Cancer is the most common cause of death and morbidity in Europe. New therapeutic targets to combat this disease are critical. Across many solid cancers, poor prognosis largely correlates with the infiltration of tumour-associated macrophages (TAMs). TAMs enhance tumour progression and complicate various anticancer therapies. Although macrophages primarily employ amoeboid migration for homeostasis and immune functions, TAMs primarily utilize mesenchymal migration. Experiments in mice revealed that blockade of TAM mesenchymal migration lowers infiltration within tumours and reduces tumour growth. Targeting this distinctive feature has the potential to limit TAM recruitment in tumours and halt disease progression, while preserving healthy macrophage functions. The mesenchymal migratory mode involves podosomes and is characterized by integrin-mediated adherence to the surrounding extracellular matrix (ECM), and the requirement of ECM proteolysis. In sharp contrast, amoeboid migration is independent of podosomes and integrins. We will investigate and evaluate the potential of targeting integrin signaling as a new strategy to manipulate TAM infiltration into tumours. Elegant knock-in and knockout mouse models will be used to establish the key regulators of integrin signaling in TAM mesenchymal migration. This novel paradigm will be extended to TAM migration in human breast tumour specimens. We will also provide new insights at the subcellular level by exploring the roles of integrin signaling in the formation and function of podosomes. Our study endeavours to identify novel and unanticipated avenues for blockade of TAM mesenchymal migration and tumour infiltration to synergize with current combination therapies that simultaneously target both pro-tumour stromal cells and cancer cells. Targeting mesenchymal migration in macrophages could have far-reaching implications beyond cancer in other disease contexts that involve macrophages including chronic inflammation.


Net EU contribution
€ 116 953,92
75794 Paris

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Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
Total cost
€ 116 953,92