Abstract
Colorectal cancer liver metastasis (CRLM) is a leading cause of mortality, driven by poorly defined molecular interactions within the hepatic niche. Here, we identify a distinct population of pro-metastatic Early Growth Response 1 (Egr1)+ neutrophils that accumulate in the pre-metastatic liver. Mechanistically, we show that KIAA1199-high cancer cells secrete granulin-rich extracellular vesicles, which are internalized by hepatocytes. This uptake triggers a subset of functionally reprogrammed hepatocytes, characterized by a profound metabolic reprogramming and the suppression of peroxisome proliferator-activated receptor gamma (PPARγ) signaling, leading to increased secretion of Serum Amyloid A2 (SAA2). Hepatocyte-derived SAA2 subsequently activates Formyl Peptide Receptor 2 (FPR2) on neutrophils, stabilizing Egr1-driven transcriptional program via the PI3K-AKT pathway to enhance neutrophil survival and pro-angiogenic activity. These Egr1+ neutrophils co-localize with reprogrammed hepatocytes at the tumor-liver interface, where they promote vascular remodeling to facilitate metastatic colonization. Pharmacological restoration of PPARγ or FPR2 inhibition abrogate CRLM in preclinical models in female mice. Furthermore, a combined KIAA1199-SAA2 signature predicts liver metastasis risk in patients. Our findings delineate a KIAA1199-PPARγ/SAA2-Egr1 axis orchestrating the pre-metastatic niche and propose metabolic normalization as a preventative strategy for liver metastasis.
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Data availability
The publicly available data used in this study are available in the Gene Expression Omnibus (GEO) under accession code GSE225857, the National Omics Data Encyclopedia (NODE) under accession code OEP00001756, and The Cancer Genome Atlas (TCGA) Pan-Cancer dataset (https://www.cancer.gov/tcga). The single-cell RNA-sequencing data generated in this study have been deposited in the Genome Sequence Archive (GSA) under the accession code PRJCA046174. The proteomics and transcriptomics data generated in this study have been deposited in the iProX database under accession code IPX0014830000 and are also available at Zenodo under https://doi.org/10.5281/zenodo.18205510. The remaining data are available within the Article, Supplementary Information, or Source Data file, and/or are available from the corresponding author upon reasonable request. Source data are provided with this paper.
Code availability
All data analyses and processing were performed using publicly available software and established packages, as detailed and cited in the Methods section. The code used in this study has been deposited in Zenodo under https://doi.org/10.5281/zenodo.18205510.
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Acknowledgements
The authors thank the patients who participated in this study. This work is supported by the National Natural Science Foundation of China (82272711 to D.J.Z., 82272900 to L.Z., and 82573302, 82373050 to T.Z.).
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L.S.L., K.C., P.Y.Z., G.J.X., and J.G.Z. conducted experiments. L.S.L., K.C., and D.J.Z. wrote the manuscript. L.Z. and D.J.Z. designed research studies and analyzed data. Z.Y.L., D.D.Y., J.Z., P.F.Z., and J.H.R. acquired data. D.J.Z. and Z.T. supervised the project.
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Li, L., Zhao, L., Cao, K. et al. Hepatocytes functionally reprogrammed by KIAA1199-high colorectal cancer cells favour the accumulation of pro-metastatic Egr1+ neutrophils. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69250-1
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DOI: https://doi.org/10.1038/s41467-026-69250-1
