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<p>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)<sup>+</sup> 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<sup>+</sup> 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.</p>

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Hepatocytes functionally reprogrammed by KIAA1199-high colorectal cancer cells favour the accumulation of pro-metastatic Egr1+ neutrophils

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月7日

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  • Lisha Li,
  • Lei Zhao,
  • Kui Cao,
  • Peiyi Zhang,
  • Guojie Xu,
  • Jinge Zheng,
  • Zhenyu Lin,
  • Dandan Yu,
  • Jinghua Ren,
  • Jing Zhang,
  • Pengfei Zhou,
  • Tao Zhang,
  • Dejun Zhang

摘要

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.