Abstract P01: Investigating the Early-stage Colorectal Cancer Liver Metastasis Microenvironment to Discover Novel Macrophage Molecular Targets

Abstract Colorectal cancer (CRC) is the second-leading cause of cancer deaths in Singapore for both men and women, accounting for more than 4000 deaths between 2016 and 2020. Up to 50% of patients diagnosed with CRC eventually develop liver metastasis, which is the spread of the patient’s cancer to the liver. Liver metastasis is notoriously difficult to treat and a major cause of death for CRC patients. Hence, there remains a pressing clinical need for novel preventive and treatment strategies of liver metastasis in CRC. In the liver, there is a complex milieu of different cell types, including liver-resident macrophages known as Kupffer cells that derive from embryonic precursors and pre-exist in the tissue before cancer onset, and monocyte-derived macrophages that are recruited during cancer progression. As these macrophage populations with distinct origins and time spent in tissues are endowed with different functions and occupy distinct spatial niches, an in-depth study of these distinct macrophage populations in CRC liver metastasis has the potential to discover novel strategies to prevent and treat the disease. Our study focused on the early-stage liver microenvironment after the seeding of metastatic CRC cells in the liver. We first developed an orthotopic CRC liver metastasis mouse model that involves the hemisplenic injection of murine CRC cells such that CRC cells seed in the liver from the bloodstream. We then used granulocyte-monocyte progenitor fate-mapping mice to track the infiltration of monocyte-derived macrophages into the diseased liver during early-stage CRC liver metastasis independently from the Kupffer cells. Thirdly, we used transgenic mouse strains to selectively deplete Kupffer cells and not monocyte-derived macrophages during early-stage CRC liver metastasis. Finally, we performed single-cell sequencing and spatial analysis on both immune and non-immune cells in the early-stage CRC liver metastasis microenvironment to discover novel macrophage molecular targets. Citation Format: William W Ho, Ziyi Li, Hazimah M Nordin, Gowshika Rengasamy, Katharine Yang, Satish K Tiwari, Sulvania Susanto, Darren Chua, Zheng Li, Leonard Tan, Denise Ong, Victor Ho, Melissa S. F. Ng, Pierce Kah Hoe Chow, Shu Zhen Chong, Kong Peng Lam, Florent Ginhoux. Investigating the Early-stage Colorectal Cancer Liver Metastasis Microenvironment to Discover Novel Macrophage Molecular Targets [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P01.