Descrizione del progetto
Macrofagi nelle metastasi epatiche
Le metastasi epatiche sono un evento comune in diversi tipi di cancro e i macrofagi sembrano svolgere un ruolo chiave nella regolazione delle risposte immunitarie antitumorali. Tuttavia, la diversità dei macrofagi nelle metastasi epatiche è ancora poco conosciuta e ciò ostacola la capacità di modularli efficacemente nel contesto della terapia antitumorale. Finanziato dal programma di azioni Marie Sklodowska-Curie, il progetto MetaMacNiche si propone di studiare la specializzazione funzionale delle cellule Kupffer residenti nel fegato e dei macrofagi associati al tumore derivati dai monociti durante le metastasi epatiche. Attraverso tecnologie all’avanguardia, i ricercatori identificheranno le interazioni chiave cellula-cellula coinvolte nella riprogrammazione dei macrofagi e valuteranno il potenziale di modulazione dell’attività dei macrofagi per migliorare la risposta all’immunoterapia.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Meccanismo di finanziamento
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinatore
9052 ZWIJNAARDE - GENT
Belgio