文章：

gemini -过表达的三阴性乳腺癌细胞特异性归巢到肺部的分子基础

The molecular underpinning of geminin-overexpressing triple-negative breast cancer cells homing specifically to lungs 

原文发布日期：2021-03-15 

英文摘要：

Triple-negative breast cancer (TNBCs) display lung metastasis tropism. However, the mechanisms underlying this organ-specific pattern remains to be elucidated. We sought to evaluate the utility of blocking extravasation to prevent lung metastasis. To identify potential geminin overexpression-controlled genetic drivers that promote TNBC tumor homing to lungs, we used the differential/suppression subtractive chain (D/SSC) technique. A geminin overexpression-induced lung metastasis gene signature consists of 24 genes was discovered. We validated overexpression of five of these genes (LGR5, HAS2, CDH11, NCAM2, and DSC2) in worsening lung metastasis-free survival in TNBC patients. Our data demonstrate that LGR5-induced β-catenin signaling and stemness in TNBC cells are geminin-overexpression dependent. They also demonstrate for the first-time expression of RSPO2 in mouse lung tissue only and exacerbation of its secretion in the circulation of mice that develop geminin overexpressing/LGR5+-TNBC lung metastasis. We identified a novel extravasation receptor complex, consists of CDH11, CD44v6, c-Met, and AXL on geminin overexpressing/LGR5+-TNBC lung metastatic precursors, inhibition of any of its receptors prevented geminin overexpressing/LGR5+-TNBC lung metastasis. Overall, we propose that geminin overexpression in normal mammary epithelial (HME) cells promotes the generation of TNBC metastatic precursors that home specifically to lungs by upregulating LGR5 expression and promoting stemness, intravasation, and extravasation in these precursors. Circulating levels of RSPO2 and OPN can be diagnostic biomarkers to improve risk stratification of metastatic TNBC to lungs, as well as identifying patients who may benefit from therapy targeting geminin alone or in combination with any member of the newly discovered extravasation receptor complex to minimize TNBC lung metastasis. 

摘要翻译： 

三阴性乳腺癌（TNBC）表现出肺转移倾向性，但其器官特异性模式的潜在机制尚未明确。本研究旨在评估阻断外渗过程对预防肺转移的效用。为识别geminin过表达调控的、促进TNBC肿瘤向肺部归巢的潜在遗传驱动因子，我们采用差异/抑制消减链（D/SSC）技术，发现了一个由24个基因构成的geminin过表达诱导肺转移特征谱。在TNBC患者中，我们验证了其中五个基因（LGR5、HAS2、CDH11、NCAM2和DSC2）的过表达与肺转移无生存期恶化相关。数据表明，LGR5诱导的β-连环蛋白信号通路和TNBC细胞的干性特征具有geminin过表达依赖性。研究首次发现RSPO2仅在小鼠肺组织中表达，且在发生geminin过表达/LGR5阳性TNBC肺转移的小鼠循环系统中其分泌量加剧。我们鉴定了一个新型外渗受体复合体，由CDH11、CD44v6、c-Met和AXL组成，存在于geminin过表达/LGR5阳性TNBC肺转移前体细胞上，抑制其中任一受体均可阻止肺转移发生。总体而言，我们提出：正常乳腺上皮细胞（HME）中geminin的过表达通过上调LGR5表达并增强前体细胞的干性、内渗和外渗能力，促进了特异性向肺部归巢的TNBC转移前体细胞的生成。循环系统中的RSPO2和OPN水平可作为诊断生物标志物，用于改善TNBC肺转移的风险分层，并识别可能从单独靶向geminin或联合靶向新发现的外渗受体复合体任何成员的治疗中获益的患者，从而最大限度减少TNBC肺转移。

原文链接：

The molecular underpinning of geminin-overexpressing triple-negative breast cancer cells homing specifically to lungs