Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
Sci Immunol. 2024 Jun 14;9(96):eadh5462. doi: 10.1126/sciimmunol.adh5462.
Expression of the long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 () correlates with tumor progression and metastasis in many tumor types. However, the impact and mechanism of action by which promotes metastatic disease remain elusive. Here, we used CRISPR activation (CRISPRa) to overexpress in patient-derived lung adenocarcinoma (LUAD) cell lines and in the autochthonous K-ras/p53 LUAD mouse model. overexpression was sufficient to promote the progression of LUAD to metastatic disease in mice. Overexpression of enhanced cell mobility and promoted the recruitment of protumorigenic macrophages to the tumor microenvironment through paracrine secretion of CCL2/Ccl2. up-regulation was the result of increased global chromatin accessibility upon overexpression. Macrophage depletion and Ccl2 blockade counteracted the effects of overexpression. These data demonstrate that a single lncRNA can drive LUAD metastasis through reprogramming of the tumor microenvironment.
长链非编码 RNA（lncRNA）转移相关肺腺癌转录本 1（）的表达与多种肿瘤类型的肿瘤进展和转移相关。然而，促进转移疾病的机制仍不清楚。在这里，我们使用 CRISPR 激活（CRISPRa）在患者来源的肺腺癌（LUAD）细胞系中和自发的 K-ras/p53 LUAD 小鼠模型中过表达。过表达足以促进 LUAD 在小鼠中进展为转移性疾病。过表达促进了 LUAD 细胞的迁移能力，并通过旁分泌 CCL2/Ccl2 促进了促肿瘤巨噬细胞向肿瘤微环境的募集。上调是由于过表达后全局染色质可及性增加所致。巨噬细胞耗竭和 Ccl2 阻断拮抗了过表达的作用。这些数据表明，单个 lncRNA 可以通过重塑肿瘤微环境来驱动 LUAD 转移。
