Leucine-Rich Alpha-2-Glycoprotein 1 Promotes Metastatic Colorectal Cancer Growth Through Human Epidermal Growth Factor Receptor 3 Signaling

Authors

Moeez Rathore
Kimberly Curry
Wei Huang
Michel'le Wright
Daniel Martin
Jiyeon Baek
Derek Taylor
Masaru Miyagi
Wen Tang
Hao Feng
Yamu Li
Zhenghe Wang
Hallie Graor
Joseph Willis
Elizabeth Bryson
Christina S Boutros
Omkar Desai
Bianca N Islam
Lee M Ellis
Stephen E Moss
Jordan M Winter
John Greenwood
Rui Wang

Publication Date

2-1-2025

Journal

Gastroenterology

DOI

10.1053/j.gastro.2024.10.004

PMID

39393543

PMCID

PMC11769768

PubMedCentral® Posted Date

2-1-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background & aims: Therapy failure in patients with metastatic colorectal cancer (mCRC, ∼80% occur in the liver) remains an overarching challenge. Preclinical studies demonstrated that human epidermal growth factor receptor 3 (HER3) promotes colorectal cancer (CRC) cell survival, but therapies blocking the neuregulin-induced canonical HER3 signaling have made little impact in the clinic. Recent studies suggest that the liver microenvironment promotes CRC growth by activating HER3 in a neuregulin-independent fashion, thus elucidation of these mechanisms may reveal new strategies for treating patients with mCRC.

Methods: Patient-derived primary liver endothelial cells (ECs) were used to interrogate EC-CRC crosstalk. We conducted proteomic analysis to identify EC-secreted factor(s) that triggers noncanonical HER3 activation in CRC and determined the subsequent effects on mCRC using diverse murine mCRC models. In vitro studies with genetic and pharmacological interventions were used to map the noncanonical HER3 pathway.

Results: We demonstrated that EC-secreted leucine-rich alpha-2-glycoprotein 1 (LRG1) directly binds and activates HER3 and promotes CRC growth distinct from neuregulin, the canonical HER3 ligand. Blocking host-derived LRG1 by gene knockout or a neutralizing antibody impaired mCRC outgrowth in the liver and prolonged mouse survival. We identified protein synthesis activated by the PI3K-PDK1-RSK-eIF4B axis as the biologically relevant signaling cascade downstream of the LRG1-HER3 interaction, which was not blocked by conventional HER3-specific antibodies that failed in prior clinical trials.

Conclusions: LRG1 is a novel HER3 ligand and mediates liver-mCRC crosstalk. The LRG1-HER3 signaling axis is distinct from canonical HER3 signaling and represents a new therapeutic opportunity to treat patients with mCRC, and potentially other types of liver metastases.

Keywords

Humans, Colorectal Neoplasms, Animals, Signal Transduction, Receptor, ErbB-3, Liver Neoplasms, Mice, Glycoproteins, Cell Proliferation, Endothelial Cells, Liver, Proteomics, Cell Line, Tumor, Female, Tumor Microenvironment, liver microenvironment, GI cancer, liver metastases, paracrine

Published Open-Access

yes

Recommended Citation

Rathore, Moeez; Curry, Kimberly; Huang, Wei; et al., "Leucine-Rich Alpha-2-Glycoprotein 1 Promotes Metastatic Colorectal Cancer Growth Through Human Epidermal Growth Factor Receptor 3 Signaling" (2025). Faculty, Staff and Student Publications. 1197.
https://digitalcommons.library.tmc.edu/uthsph_docs/1197