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. 2025 Feb;168(2):300-315.e3.
doi: 10.1053/j.gastro.2024.10.004. Epub 2024 Oct 10.

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

Moeez Rathore  1 , Kimberly Curry  1 , Wei Huang  2 , Michel'le Wright  1 , Daniel Martin  3 , Jiyeon Baek  4 , Derek Taylor  5 , Masaru Miyagi  2 , Wen Tang  6 , Hao Feng  7 , Yamu Li  8 , Zhenghe Wang  9 , Hallie Graor  1 , Joseph Willis  10 , Elizabeth Bryson  11 , Christina S Boutros  12 , Omkar Desai  12 , Bianca N Islam  13 , Lee M Ellis  14 , Stephen E Moss  15 , Jordan M Winter  16 , John Greenwood  15 , Rui Wang  17
Affiliations

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

Moeez Rathore et al. Gastroenterology. 2025 Feb.

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: GI Cancer; Liver Metastases; Liver Microenvironment; Paracrine.

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Conflict of interest statement

J.G. and S.E.M. are founders of Senya Therapeutics, a company spun out by UCL Business to commercialize a LRG1 function-blocking therapeutic antibody developed through the UK Medical Research Council DPFS funding scheme. J.G. and S.E.M. are members of the scientific advisory board, shareholders of this company, and named inventors on three patents related to LRG1 as a therapeutic target. There is no conflict of interest for all other authors.

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