PO.CL01.22 · 临床研究
癌-神经元相互作用启动EGFR突变型NSCLC的神经模拟及脑定植
Cancer-neuron interaction initiates neural mimicry and brain colonization in EGFR-mutant NSCLC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
脑转移是非小细胞肺癌(NSCLC)患者的一项重大临床挑战，携带EGFR突变肿瘤的NSCLC患者中枢神经系统(CNS)受累风险增加，多达50-60%的患者会发生CNS转移。转移至脑部是一个复杂的多步骤过程，其中肿瘤细胞必须穿过血脑屏障并适应独特的CNS环境。近期小细胞肺癌(SCLC)研究提示，与肺部原发肿瘤相比，定居于脑部的肺癌细胞获得了神经样转录组程序。鉴于EGFR突变型NSCLC肿瘤细胞可通过包括上皮-间质转化(EMT)及SCLC或神经内分泌转化在内的过程表现出谱系可塑性，作为对EGFR抑制剂获得性治疗耐药的一部分，我们假设EGFR突变型NSCLC细胞可能与神经元细胞相互作用以促进CNS转移及谱系改变。此处，我们使用体外及体内模型评估神经元相互作用对EGFR突变型NSCLC细胞的影响。我们分离了原代小鼠神经元，并将其与HCC827、HCC4006及H1975 EGFR突变型NSCLC细胞共培养。两天后，神经元标志物NeuN及MAP2的免疫荧光染色显示，与神经元共培养的EGFR突变型肿瘤细胞上调了这些神经元标志物的表达，而单独生长的肿瘤细胞则没有。我们的EGFR突变型NSCLC脑肿瘤体内模型支持，暴露于神经元相互作用的癌细胞中神经元、突触及轴突基因的富集。此外，我们对人EGFR突变型NSCLC脑肿瘤与配对的原发肺肿瘤进行了空间转录组分析，以评估与脑转移相关的肿瘤微环境(TME)区室的改变。综上，我们提出神经模拟可能是EGFR突变型NSCLC细胞在脑微环境中生长时所利用的一种潜在机制。我们的研究进一步揭示了破坏癌-神经元相互作用以抑制EGFR突变型NSCLC脑转移生长的新靶点。
查看英文原文 English abstract
Brain metastasis is a major clinical challenge for patients with non-small cell lung cancer (NSCLC), and NSCLC patients with tumors harboring EGFR mutations have an increased risk of central nervous system (CNS) involvement, with up to 50-60% of patients developing CNS metastasis. The process of metastasizing to the brain is a complex multistep process in which tumor cells must cross the blood-brain barrier and adapt to the unique CNS environment. Recent studies in small cell lung cancer (SCLC) suggested that lung cancer cells residing in the brain acquired neural-like transcriptomic programs as compared to primary tumors in the lung. Given that EGFR mutant NSCLC tumor cells can exhibit lineage plasticity through processes including epithelial to mesenchymal transition (EMT) and SCLC or neuroendocrine transformation as part of acquired therapeutic resistance to EGFR inhibitors, we hypothesized that EGFR mutant NSCLC cells may interact with neuronal cells to facilitate CNS metastasis and lineage change. Here, we used in vitro and in vivo models to evaluate the impact of neuronal interaction on EGFR mutant NSCLC cells. We isolated primary murine neurons and co-cultured them with HCC827, HCC4006, and H1975 EGFR mutant NSCLC cells. After two days, immunofluorescent staining for neuronal markers, NeuN and MAP2, showed that EGFR mutant tumor cells co-cultured with neurons upregulated expression of these neuronal markers whereas tumor cells grown alone did not. Our in vivo models of EGFR mutant NSCLC brain tumors supported the enrichment of neuronal, synaptic, and axonal genes in cancer cells exposed to neuronal interaction. Moreover, we performed spatial transcriptomic analysis of human EGFR mutant NSCLC brain tumors paired with primary lung tumors to evaluate alteration of tumor microenvironment (TME) compartments associated with brain metastasis. Together, we propose neural mimicry as a potential mechanism exploited by EGFR-mutant NSCLC cells growing in the brain microenvironment. Our study further sheds light on novel targets for disrupting cancer-neuron interaction to inhibit the growth of brain metastasis in EGFR mutant NSCLC.
利益披露 Disclosure
S. Song, None.