富含亮氨酰的α-2-糖蛋白1通过表皮生长因子受体3（HER3）信号促进转移性结直肠癌的生长

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

GASTROENTEROLOGY

影响因子:25.1

分区:医学1区 Top / 胃肠肝病学1区

发表日期:2025 Feb

作者: 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

DOI: 10.1053/j.gastro.2024.10.004

摘要

转移性结直肠癌（mCRC，约80%的病例发生在肝脏）患者的治疗失败仍然是巨大挑战。前期研究表明，人类表皮生长因子受体3（HER3）促进结直肠癌（CRC）细胞存活，但阻断神经酰胺诱导的HER3经典信号的治疗在临床上效果有限。最新研究表明，肝脏微环境通过非神经酰胺依赖的方式激活HER3，促进CRC的生长，因此解析这些机制可能揭示新的治疗策略。我们利用患者源性原发性肝内皮细胞（ECs）研究EC-CRC的交互作用。通过蛋白质组分析，鉴定出触发非经典HER3激活的EC分泌因子，并用多种小鼠模型研究其对mCRC的影响。利用基因和药理干预的体外实验，绘制了非经典HER3信号通路。研究发现，EC分泌的亮氨酰-α-2-糖蛋白1（LRG1）可直接结合并激活HER3，促进CRC的生长，与经典HER3配体神经酰胺不同。阻断宿主源性LRG1（通过基因敲除或中和抗体）显著抑制肝脏中mCRC的扩展，延长小鼠存活时间。我们还发现，PI3K-PDK1-RSK-eIF4B轴介导的蛋白质合成是LRG1-HER3相互作用的生物学相关信号级联，不受传统HER3特异性抗体的阻断。这表明LRG1是一个新型HER3配体，介导肝脏-CRC的交互作用，代表治疗mCRC和其他肝转移的潜在新靶点。

Abstract

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.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.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.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.