H2020Индивидуална стипендия2019–2021

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

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2019-11-01 → 2021-10-31
Финансиране от ЕС: 116 954 €
Участници: 1
Схема: MSCA-IF-EF-RI

Линиите свързват координатора с партньорите.

Накратко на български

Вътреклеточните сигнали, които позволяват на макрофагите да се придвижват през плътни тъкани чрез специални структури, се анализират в туморите. Това помага да се ограничи навлизането на тези имунни клетки в рака, без да се увреждат нормалните им функции в тялото.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

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

Macrophages are innate immune cells that are present in all tissues of the body to maintain tissue homeostasis and immune surveillance. In several pathological conditions, including infection, injury, and inflammation, macrophages derived from blood monocytes are recruited to tissues and either participate in disease resolution and tissue repair or aid in progression of disease as in chronic inflammation. Macrophages are also massively recruited in the majority of solid tumours. The poor prognosis is largely correlated with the infiltration of tumour-associated macrophages. They promote tumour progression and interfere with the effectiveness of various anti-cancer therapies. Unsurprisingly, therapies that aim to either deplete or reprogram macrophages deserve considerable attention. However, care should be taken when modulating immune responses so as not to interfere with essential macrophage functions. Remarkably, all immune cells use amoeboid migration, and macrophages are able to use the mesenchymal mode of migration in dense tissues and most tumours. Unlike the amoeboid mode, mesenchymal migration requires podosomes which are specialized cellular structures involved in integrin-mediated cell adhesion. This feature deserves attention in order to specifically limit the recruitment of macrophages into tumours to neutralize their roles in disease progression, while preserving healthy macrophage functions. Integrin adhesion receptors are proven therapeutic targets in many diseases; however, complete blockage of their function often leads to mechanism-based toxicity limiting the use of integrin antagonists. The Macrophint project aimed to target the intracellular signaling pathways that orchestrate the integrin-dependent mesenchymal migration of macrophages. This strategy aligns with the emerging paradigm that signaling events in blood cells operate in both a cell-type and integrin-specific manner, providing unique pathways to manipulate immune cell recruitment into specific tissues. The Macrophint research program devised novel and unanticipated avenues to block mesenchymal macrophage migration and tumour infiltration to synergize with combination therapies that simultaneously target pro-tumour stromal cells and cancer cells. In addition, the individual Marie Sklodowska Curie Actions fellowship was also intended to promote the career of the beneficiary researcher and to contribute to raising public awareness of the research work carried out.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisКоординаторФранция