Distinct and cooperative roles of host and tumor Osteopontin in colorectal cancer liver metastasis
Czabala, P.; Zhao, Y.; Klement, J. D.; Redd, P. S.; Poschel, D.; Carver, K.; Fick, K.; Tiamiyu, Z.; Zoccheddu, M.; Schoenlein, P.; Waller, J.; Shi, H.; Liu, K.
Show abstract
Osteopontin (OPN) is a secreted phosphoprotein implicated in colorectal cancer liver metastasis (CRCLM), yet the distinct spatial contributions of host-and tumor-derived OPN in driving this disease remain unclear. Using a 2 x 2 genetic knockout mouse model targeting OPN in host and tumor compartments, combined with spatial transcriptomics, we investigated compartment-specific OPN functions in CRCLM. Tumor-derived OPN promotes tumor proliferation through MEK/ERK signaling. Host OPN licenses monocyte-to-macrophage differentiation, while tumor OPN polarizes macrophages towards an M2-like state. Both host and tumor OPN suppress T cells in the tumor microenvironment, whereas loss of host OPN reveals an interferon-driven, anti-tumor niche. Translational studies using OPN-blockade immunotherapy in syngeneic and patient-derived xenograft mouse models reduced tumor burden and enhanced T cell infiltration. Together, these findings redefine the OPN-myeloid paradigm in CRC and nominate OPN as a potential therapeutic target.
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