富含亮氨酸的α-2-糖蛋白1通过人表皮生长因子受体3信号传导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
影响因子:25.10000
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
摘要
转移性结直肠癌患者的治疗衰竭（MCRC，肝脏中约80％）仍然是一个总体挑战。临床前研究表明，人表皮生长因子受体3（HER3）促进了结直肠癌（CRC）细胞存活，但是阻止神经蛋白诱导的规范HER3信号传导的疗法对诊所的影响很小。最近的研究表明，肝微环境通过以神经依赖性的方式激活HER3来促进CRC的生长，因此阐明这些机制可能揭示了用于治疗MCRC的患者的新策略。患者使用了patient剂的原发性肝内皮细胞（ECS）来询问EC-CRC CROSCCRC CROSSTALK。我们进行了蛋白质组学分析，以鉴定EC分泌的因子，从而触发CRC中的非规范HER3激活，并使用多种鼠MCRC模型确定了随后对MCRC的影响。使用遗传学和药理干预措施的体外研究来绘制非规范的HER3途径。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生长与Neuregulin不同的CRC生长。通过基因基因敲除或中和抗体阻止宿主衍生的LRG1，肝脏中的MCRC生长会损害肝脏的生存和延长小鼠的生存率。 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. LRG1-HER3信号轴不同于规范HER3信号传导，代表了治疗MCRC患者以及可能其他类型的肝转移的新的治疗机会。
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.