转移性结直肠癌（mCRC，约 80% 发生在肝脏）患者的治疗失败仍然是一个首要挑战。临床前研究表明，HER3 可促进 CRC 细胞存活，但阻断神经调节蛋白诱导的经典 HER3 信号传导的疗法在临床上效果甚微。最近的研究表明，肝脏微环境通过以不依赖神经调节蛋白的方式激活 HER3 来促进 CRC 生长，因此阐明这些机制可能会揭示治疗 mCRC 患者的新策略。患者来源的原代肝内皮细胞 (EC) 用于研究 EC -CRC串扰。我们进行了蛋白质组学分析，以确定在 CRC 中触发非典型 HER3 激活的 EC 分泌因子，并使用不同的小鼠 mCRC 模型确定了对 mCRC 的后续影响。采用遗传和药理学干预的体外研究来绘制非典型 HER3 通路。我们证明，与神经调节蛋白不同，EC 分泌的富含亮氨酸的 α-2-糖蛋白 1 (LRG1) 直接结合并激活 HER3，并促进 CRC 生长。典型的 HER3 配体。通过基因敲除或中和抗体阻断宿主来源的 LRG1 会损害肝脏中 mCRC 的生长并延长小鼠的存活时间。我们确定由 PI3K-PDK1-RSK-eIF4B 轴激活的蛋白质合成是 LRG1-HER3 相互作用下游的生物学相关信号级联，该信号级联不会被先前临床试验中失败的传统 HER3 特异性抗体阻断。 HER3 配体并介导肝脏-mCRC 串扰。 LRG1-HER3 信号传导轴与经典 HER3 信号传导不同，代表了治疗 mCRC 和潜在其他类型肝转移患者的新治疗机会。版权所有 © 2024 AGA Institute。由爱思唯尔公司出版。保留所有权利。

Therapy failure in patients with metastatic colorectal cancer (mCRC, ∼80% occur in the liver) remains an overarching challenge. Preclinical studies demonstrated that HER3 promotes 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 non-canonical 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 non-canonical 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.Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.