Therapeutic induction of mesenchymal-epithelial transition via epigenetic reprogramming curtails metastatic progression and sensitizes breast cancers to treatment [RNA-seq]

The epithelial-mesenchymal transition (EMT) is a developmental program that is co-opted by tumor cells to aid in their embarking on the metastatic cascade. Tumor cells that undergo EMT are known to be endowed by, amongst other traits, heightened resistance to chemotherapy. Despite a clear understanding of the role played by the EMT program in conferring cells with these aggressive traits, there are currently no therapeutic avenues specifically targeting the program. Here we show that treatment of mesenchymal-like breast cancer cells with eribulin, an FDA-approved drug for the treatment of advanced breast cancers, leads to a mesenchymal-epithelial transition (MET), accompanied by a loss of metastatic propensity and sensitization of tumor cells to subsequent rounds of chemotherapy. We uncover a novel alternate mechanism of action that provides evidence for eribulin pretreatment as a viable clinical mechanism of MET induction that curtails metastatic progression and the evolution of therapy resistance. Overall design: RNA-seq. PB3-Parental and PB3-resistant derivatives; erubilin, paclitaxel, or vinorelbine treatment. Paired-end RNA-sequencing of three replicates per cell line.

上皮间质转化（epithelial-mesenchymal transition, EMT）是一类发育程序，肿瘤细胞可劫持该程序以启动自身的转移级联反应。已知发生EMT的肿瘤细胞除其他特性外，还获得了增强的化疗耐药性。尽管学界已明确阐明EMT程序在赋予细胞这些侵袭性表型中的作用，但目前尚无专门靶向该程序的治疗策略。
本研究显示，使用艾立布林（eribulin）——一种获美国食品药品监督管理局（Food and Drug Administration, FDA）批准的晚期乳腺癌治疗药物——处理间质样乳腺癌细胞，可诱导间质上皮转化（mesenchymal-epithelial transition, MET），同时伴随肿瘤细胞转移能力丧失以及对后续化疗的敏感性恢复。本研究揭示了一种全新的艾立布林作用机制，证实艾立布林预处理可作为诱导MET的可行临床策略，从而抑制肿瘤转移进展及治疗耐药性的演化。
整体实验设计：转录组测序（RNA-seq）。实验分组包括PB3亲本细胞及其PB3耐药衍生细胞；分别用艾立布林、紫杉醇（paclitaxel）或长春瑞滨（vinorelbine）处理。每个细胞系设置三个生物学重复，进行双端RNA测序（paired-end RNA-sequencing）。