Spatial multi-omics analysis reveals vimentin-high macrophages-endothelial cells niche shapes CAFs heterogeneity in colorectal cancer metastasis
The spatial architecture of the tumor microenvironment (TME) is pivotal in the progression of colorectal cancer (CRC) liver metastasis. By applying high-plex spatial multi-omic mapping and neighborhood analysis to a discovery cohort of colorectal cancer primary tumor (PT) and paired liver metastases (LM), we identified a specialized vimentin-high macrophages-endothelial cells niche that…
Colorectal cancer (CRC) liver metastasis is influenced by the spatial organization of the tumor microenvironment (TME). A high-plex spatial multi-omic mapping technique, coupled with neighborhood analysis of colorectal cancer primary tumor (PT) and liver metastases (LM) samples, revealed a unique vimentin-high macrophages-endothelial cells niche that dictates cancer-associated fibroblast (CAF) traits.
In the primary tumors, vimentin-high macrophages release INHBA, activating the ACVR2/TGF-{beta} axis in endothelial cells, leading CAFs to adopt a myCAF phenotype. Meanwhile, in liver metastases, these macrophages secrete CXCL9, activating the PI3K-Akt/NF-{kcy}B/CXCL12 pathway in endothelial cells, steering CAFs towards an iCAF state.
Clinically, heightened niche activity is associated with a poor prognosis. The site-specific endothelial signaling in primary tumors versus metastatic lesions highlights distinct stromal weaknesses that could be targeted therapeutically. Notably, structural elements of the TME can be identified from standard histopathology. These results demonstrate a site-specific regulatory mechanism of the macrophage-endothelial niche, presenting a novel and clinically relevant biomarker for CRC prognosis.
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