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

## TL;DR

High KIAA1199 colorectal cancer cells reprogram liver cells to attract neutrophils that help cancer spread to the liver.

## Contribution

Identifies a new mechanism where cancer cells reprogram liver cells to promote metastasis via Egr1+ neutrophils.

## Key findings

- KIAA1199-high cancer cells secrete granulin-rich extracellular vesicles that reprogram hepatocytes.
- Reprogrammed hepatocytes secrete SAA2, which activates Egr1+ neutrophils to promote liver metastasis.
- PPARγ restoration or FPR2 inhibition reduces metastasis in mouse models.

## 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.

KIAA1199 is upregulated in colorectal cancer (CRC), associated with metastasis and poor clinical outcomes. Here the authors report that extracellular vesicles secreted by KIAA1199-high CRC cells functionally reprogram hepatocytes to support the infiltration of Egr1+ neutrophils, resulting in accelerated liver metastatic colonization.