Rathore Moeez, Curry Kimberly, Huang Wei, Wright Michel'le, Martin Daniel, Baek Jiyeon, Taylor Derek, Miyagi Masaru, Tang Wen, Feng Hao, Li Yamu, Wang Zhenghe, Graor Hallie, Willis Joseph, Bryson Elizabeth, Boutros Christina S, Desai Omkar, Islam Bianca N, Ellis Lee M, Moss Stephen E, Winter Jordan M, Greenwood John, Wang Rui
Department of Surgery, Case Western Reserve University, Cleveland, Ohio; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio.
Gastroenterology. 2025 Feb;168(2):300-315.e3. doi: 10.1053/j.gastro.2024.10.004. Epub 2024 Oct 10.
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.
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.
转移性结直肠癌（mCRC，约80%发生于肝脏）患者的治疗失败仍是一个首要挑战。临床前研究表明，人表皮生长因子受体3（HER3）可促进结直肠癌（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收效甚微。近期研究表明，肝脏微环境以一种不依赖神经调节蛋白的方式激活HER3，从而促进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。
使用患者来源的原代肝内皮细胞（ECs）来研究EC与CRC之间的相互作用。我们进行了蛋白质组学分析，以鉴定在CRC中触发非经典HER3激活的EC分泌因子，并使用多种小鼠mCRC模型确定其对mCRC的后续影响。采用基因和药物干预的体外研究来描绘非经典HER3信号通路。
我们证明，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，这与经典HER3配体神经调节蛋白不同。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的生长并延长小鼠生存期。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，而这并未被先前临床试验中失败的传统HER3特异性抗体所阻断。
LRG1是一种新型HER3配体，介导肝脏与mCRC之间的相互作用。LRG1-HER3信号轴不同于经典HER3信号传导，代表了治疗mCRC患者以及潜在其他类型肝转移患者的新治疗机会。
