基于微流控芯片平台研究CXCL12-CXCR4信号对乳腺癌干细胞转移的影响

Real-time and dynamic monitoring tumor cell metastasis is the main advantage of microfluidic platform. CXCL12-CXCR4 signaling mediated stem cell migration and homing, indicating CXCL12-CXCR4 signaling was related with breast cancer stem cell metastasis. However, there is no method to real-time monitor breast cancer stem cell migration. Our preliminary studies revealed that targeting breast cancer stem cells inhibited breast cancer metastasis (Oncotarget, 2015, accepted). In order to mimic the effect of factors in microenvironment on breast cancer cell metastasis, we successfully established several microfluidic chips for cancer metastasis study. By using microfluidic device, the aims of this study are to 1) investigate the chemotaxis of breast cancer stem cell to CXCL12 in three-dimensional culture conditions and 2) examine whether CXCL12-CXCR4 interaction enhance the migration and metastasis capability of breast cancer stem cells via inducing epithelial-mesenchymal transition. We will further explore the effect of CXCL12-CXCR4 on breast cancer stem cells in both tumor patient specimens and animal models. This study helps to advance our understanding of the mechanism of CXCL12-CXCR4 signaling regulating breast cancer stem cell metastasis and sheds light on targeting breast cancer stem cell and inhibiting cancer metastasis.

实时动态检测肿瘤细胞转移是微流控芯片平台的主要优势。CXCL12-CXCR4信号介导干细胞迁移与归巢，提示CXCL12-CXCR4可能参与乳腺癌干细胞的转移。但目前尚无手段实现实时监测乳腺癌干细胞的迁移。申请人前期发现靶向乳腺癌干细胞可同时抑制乳腺癌的转移（Oncotarget，2015，已接收），并成功构建多种微流控芯片转移模型，用于模拟肿瘤微环境中不同因素对转移的影响。在此基础上，应用微流控芯片平台，本课题旨在探索1) CXCL12在三维培养条件下对乳腺癌干细胞转移的影响；2）明确CXCL12能否通过CXCR4受体诱导肿瘤干细胞发生上皮间质转化，进而增强其转移和侵袭能力，从而系统阐明CXCL12-CXCR4信号调控乳腺癌干细胞转移的分子机制。我们还将在肿瘤病人标本和动物模型中进一步验证CXCL12-CXCR4信号对乳腺癌干细胞转移的影响，为靶向乳腺癌干细胞，抑制肿瘤转移提供新的思路。

间充质干细胞（MSCs）在肿瘤的转移过程中发挥关键作用，然而其介导肿瘤转移机制仍不清楚。因此，我们构建了微流控三维培养模型来模拟复杂的肿瘤微环境。通过仿生微流控芯片模型，我们发现MSCs能够以“cluster-sprouting-infiltrating”模式引领乳腺癌细胞的转移。进一步，我们在动物原位模型中进行了验证。机制方面，缺氧所诱导的长链非编码RNA-H19能够促进基质金属蛋白酶MMP-1的分泌，从而引领乳腺癌细胞的转移。我们的结果表明肿瘤微环境中的MSCs能促进乳腺癌细胞转移，提示MSCs可以作为一个抑制乳腺癌细胞转移潜在的靶点。