Recapitualated Crosstalk between Cerebral Metastatic Lung Cancer Cells and Brain Perivascular Tumor Microenvironment in a Microfluidic Co-Culture Chip

在微流控共培养芯片中再现脑转移肺癌细胞与脑血管周围肿瘤微环境之间的串扰

主讲人：李德重

Advanced science（IF:15.1）:2022.6.03,2201785

DOI:10.1002/advs.202201785

Abstract:        

       Non-small cell lung carcinoma (NSCLC), which affects the brain, is fatal and resistant to anti-cancer therapies. Despite innate, distinct characteristics of the brain from other organs, the underlying delicate crosstalk between brain metastatic NSCLC (BM-NSCLC) cells and brain tumor microenvironment (bTME) associated with tumor evolution remains elusive. Here, a novel 3D microfluidic tri-culture platform is proposed for recapitulating positive feedback from BM-NSCLC and astrocytes and brain-specific endothelial cells, two major players in bTME. Advanced imaging and quantitative functional assessment of the 3D tri-culture model enable real-time live imaging of cell viability and separate analyses of genomic/molecular/secretome from each subset. Susceptibility of multiple patient-derived BM-NSCLCs to representative targeted agents is altered and secretion of serpin E1, interleukin-8, and secreted phosphoprotein 1, which are associated with tumor aggressiveness and poor clinical outcome, is increased in tri-culture.

      Notably, multiple signaling pathways involved in inflammatory responses, nuclear factor kappa-light-chain-enhancer of activated B cells, and cancer metastasis are activated in BM-NSCLC through interaction with two bTME cell types. This novel platform offers a tool to elucidate potential molecular targets and for effective anti-cancer therapy targeting the crosstalk between metastatic cancer cells and adjacent components of bTME.

摘要：

   脑转移性非小细胞肺癌是致命的且容易对抗肿瘤治疗产生抗性的，尽管大脑与其他器官存在有先天的、不同的特征，但是脑转移的非小细胞肺癌与脑肿瘤微环境之间存在的潜在的微妙的联系仍然是有待发现的。在本篇文章中，我们建立了一种新的微流控3D三培养平台，这个微流控平台依赖其先进的成像以及定量技术，可以做到实时成像细胞活性，以及对各个组分的基因组/分泌组/分子组，进行准确的分析。选择临床患者源性的脑转移性非小细胞肺癌细胞与星形胶质细胞和人脑内皮质细胞这两种脑肿瘤微环境中主要的两个组成部分细胞进行共培养。结果发现共培养后肿瘤细胞对代表性靶向药物的敏感性发生了改变，同时与肿瘤预后不良相关的丝氨酸蛋白酶E1、白介素-8、磷酸化蛋白1的分泌量在此培养过程中显著增加。值得注意的是，肿瘤细胞在两种脑肿瘤微环境细胞的影响下，与免疫反应相关的、活化B细胞核因子的细胞信号通路κ-轻链增强子通路，以及和肿瘤细胞转移相关的信号通路显著被激活。此平台为阐明潜在的分子靶点和说明针对脑转移性癌细胞和脑肿瘤微环境之间存在的分子串扰，从而进行研究有效的抗癌治疗提供了一个新的工具。