Descripción del proyecto
Macrófagos en las metástasis hepáticas
Las metástasis hepáticas son habituales en diversos tipos de cáncer, y los macrófagos parecen desempeñar un papel clave en la regulación de las respuestas inmunitarias antineoplásicas. Sin embargo, la diversidad de macrófagos en las metástasis hepáticas sigue siendo poco conocida, lo cual merma la capacidad de modularlos de manera eficaz en el contexto de la terapia antineoplásica. El equipo del proyecto MetaMacNiche, financiado por las acciones Marie Sklodowska-Curie, pretende investigar la especialización funcional de las células Kupffer que residen en el hígado y los macrófagos asociados a tumores derivados de monocitos durante la metástasis hepática. Mediante el uso de tecnologías vanguardistas, los investigadores identificarán las principales interacciones entre células que intervienen en la reprogramación de los macrófagos y evaluarán las posibilidades de modular la actividad de los macrófagos para mejorar la respuesta a la inmunoterapia.
Objetivo
The liver is one the most common metastatic sites for several cancers. Unfortunately, liver metastasis patients show a particularly low response to immunotherapy. One of the main immune cells populating liver metastases are macrophages. These cells have been shown to play a key role in the regulation of anti-tumor immune responses, including response to immunotherapy. However, we still lack the capacity to modulate macrophage activity during liver metastasis, because we do not yet understand their functional diversity and do not know the molecular signals that drive the pro-tumoral activity of macrophages during liver metastasis. The host lab has recently reported a major role for cell-cell interactions within the microenvironmental niche in the development and functional specialization of liver macrophages. My preliminary data indicate that liver metastasis is accompanied with the expansion of both liver-resident Kupffer cells (KCs) and monocyte-derived tumor-associated macrophages (TAMs). Single-cell analysis in mouse and human revealed that TAMs recruited during metastasis are heterogeneous and transcriptomically different from KCs, suggesting a distinct functional specialization. The molecular pathways involved in the functional reprogramming of KCs and TAMs and their relative contribution to tumor growth, remain poorly understood. In this MetaMacNiche project, I will use a combination of cutting-edge spatial multiomic technologies, intravital microscopy, and an in vivo CRISPR screen to investigate the role of KCs and TAMs in liver metastasis. Through a combination of in silico predictions and high-throughput in vivo validations, I will identify the key cell-cell interactions involved in the functional reprogramming of KCs and TAMs during liver metastasis. Finally, I aim to perform preclinical studies to assess whether we can boost the responsiveness to immunotherapy by modulating macrophage activity during liver metastasis.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinador
9052 ZWIJNAARDE - GENT
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