Sami Eman, Bogan Danielle, Molinolo Alfredo, Koziol Jim, ElShamy Wael M
Breast Cancer Program, San Diego Biomedical Research Institute, San Diego, CA, USA.
School of Public Health, Department of Epidemiology & Biostatistics, Jackson State University, Jackson, United States.
Cancer Gene Ther. 2022 Mar;29(3-4):304-325. doi: 10.1038/s41417-021-00311-x. Epub 2021 Mar 15.
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.
三阴性乳腺癌（TNBC）表现出肺转移趋向性。然而，这种器官特异性模式背后的机制仍有待阐明。我们试图评估阻断外渗以预防肺转移的效用。为了确定潜在的由geminin过表达控制的促进TNBC肿瘤归巢至肺的基因驱动因素，我们使用了差异/抑制消减链（D/SSC）技术。发现了一个由24个基因组成的geminin过表达诱导的肺转移基因特征。我们验证了其中五个基因（LGR5、HAS2、CDH11、NCAM2和DSC2）的过表达会使TNBC患者无肺转移生存期恶化。我们的数据表明，LGR5诱导的TNBC细胞中的β-连环蛋白信号传导和干性是geminin过表达依赖性的。它们还首次证明RSPO2仅在小鼠肺组织中表达，并且在发生geminin过表达/LGR5-TNBC肺转移的小鼠循环中其分泌增加。我们在geminin过表达/LGR5-TNBC肺转移前体细胞上鉴定出一种新型外渗受体复合物，其由CDH11、CD44v6、c-Met和AXL组成，抑制其任何一种受体均可预防geminin过表达/LGR5-TNBC肺转移。总体而言，我们提出正常乳腺上皮（HME）细胞中geminin过表达通过上调LGR5表达并促进这些前体细胞中的干性、内渗和外渗，从而促进特异性归巢至肺的TNBC转移前体细胞的产生。RSPO2和骨桥蛋白的循环水平可作为诊断生物标志物，以改善转移性TNBC肺转移的风险分层，以及识别可能从单独靶向geminin或与新发现的外渗受体复合物的任何成员联合治疗中受益的患者，以尽量减少TNBC肺转移。
