MetaMacNiche · Unravelling the cell-cell circuits underlying the functional reprogramming of KCs and TAMs during liver metastasis

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.