文章：

Ha-RAS诱导的侵袭性乳腺癌中关键的ETV4/Twist1/Vimentin轴

A critical ETV4/Twist1/Vimentin axis in Ha-RAS-induced aggressive breast cancer 

原文发布日期：2022-04-27 

英文摘要：

RAS oncogenes are major drivers of diverse types of cancer. However, they are largely not druggable, and therefore targeting critical downstream pathways and dependencies is an attractive approach. We have isolated a tumorigenic cell line (FE1.2), which exhibits mesenchymal characteristics, after inoculating Ha-Ras-expressing retrovirus into mammary glands of rats, and subsequently isolated a non-aggressive revertant cell line (FC5). This revertant has lost the rat Ha-Ras driver and showed a more epithelial morphology, slower proliferation in culture, and reduced tumorigenicity in vivo. Re-expression of human Ha-RAS in these cells (FC5-RAS) reinduced mesenchymal morphology, higher proliferation rate, and tumorigenicity that was still significantly milder than parental FE1.2 cells. RNA-seq analysis of FC5-RAS vs FC5-Vector cells identified multiple genes whose expressions were regulated by Ha-RAS. This analysis also identified many genes including those controlling cell growth whose expression was altered by loss of HA-Ras in FC5 cells but remained unchanged upon reintroduction of Ha-RAS. These results suggest that targeting the Ha-Ras driver oncogene induces partial tumor regression, but it still denotes strong efficacy for cancer therapy. Among the RAS-responsive genes, we identified Twist1 as a critical mediator of epithelial-to-mesenchymal transition through the direct transcriptional regulation of vimentin. Mechanistically, we show that Twist1 is induced by the ETS gene, ETV4, downstream of Ha-RAS, and that inhibition of ETV4 suppressed the growth of breast cancer cells driven by the Ha-RAS pathway. Targeting the ETV4/Twist1/Vimentin axis may therefore offer a therapeutic modality for breast tumors driven by the Ha-RAS pathway. 

摘要翻译： 

RAS癌基因是多种癌症的主要驱动因素。然而，该靶点大多难以成药，因此靶向关键下游通路和依赖性成为具有吸引力的治疗策略。我们通过向大鼠乳腺注射表达Ha-Ras的逆转录病毒，分离出具有间质特征的可致瘤细胞系（FE1.2），并进一步获得非侵袭性回复突变细胞系（FC5）。该回复突变体丢失了大鼠Ha-Ras驱动基因，呈现更典型的上皮细胞形态、体外培养增殖速度减慢且体内致瘤性降低。在这些细胞中重新表达人类Ha-RAS基因（FC5-RAS）可重新诱导间质形态转变、提高增殖速率并恢复致瘤性，但其恶性程度仍显著低于亲本FE1.2细胞。通过FC5-RAS与FC5空载体细胞的RNA-seq分析，我们鉴定出多个受Ha-RAS调控的基因。分析还发现包括控制细胞生长的基因在内的多个基因，其在FC5细胞中因HA-Ras缺失而发生表达改变，但在重新引入Ha-RAS后仍保持稳定。这些结果表明靶向Ha-Ras驱动癌基因可诱导部分肿瘤消退，但仍显示出显著的癌症治疗效力。在RAS应答基因中，我们发现Twist1通过直接转录调控波形蛋白（vimentin），成为上皮-间质转化的关键介质。机制研究表明，Twist1由Ha-RAS下游的ETS基因ETV4诱导表达，抑制ETV4可有效阻遏Ha-RAS通路驱动的乳腺癌细胞生长。因此，靶向ETV4/Twist1/波形蛋白轴可能为Ha-RAS通路驱动的乳腺肿瘤提供新型治疗策略。

原文链接：

A critical ETV4/Twist1/Vimentin axis in Ha-RAS-induced aggressive breast cancer