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

Descripción del proyecto

Un tratamiento antineoplásico basado en la inhibición de los macrófagos asociados a tumores

La infiltración de macrófagos asociados a tumores (TAM, por sus siglas en inglés) está relacionado con un mal pronóstico del cáncer. Indicios recientes señalan que la inhibición de la migración de los TAM reduce la infiltración tumoral y frena la evolución del cáncer en modelos animales. El objetivo del proyecto financiado con fondos europeos MacrophInt es desarrollar un tratamiento dirigido contra la señalización de integrinas en los TAM como nueva estrategia para modificar su infiltración en tumores. Las integrinas son esenciales para el modo migratorio mesenquimatoso de los TAM, que implica la adherencia de los podosomas celulares a la matriz extracelular circundante. La inhibición de la migración de los TAM podría emplearse junto con otros tratamientos antineoplásicos para mejorar el desenlace clínico de los pacientes.

Objetivo

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.