肺癌的脑转移导致高死亡率，但脑转移的确切机制尚不清楚。在这里，我们报道了源自肺腺癌（ADC）中CD44+肺癌干细胞（CSCs）的血管外周细胞（vascular pericytes）通过G-蛋白偶联受体124（GPR124）增强的胞内移行（TEM）引起强烈脑转移。CD44+ CSCs在血管周肠袢位生成大多数肺ADC的血管外周细胞。CSC来源的血管外周细胞样细胞（Cd-pericytes）显示出显著TEM能力，能够有效地内源化进入血管腔、存活于循环系统，在脑实质外源化，然后去分化为肿瘤发生性的CSCs形成转移灶。Cd-pericytes独特地表达GPR124，激活Wnt7-β-连环蛋白信号传导来增强Cd-pericytes的TEM能力，用于肿瘤转移的两个关键步骤：内源化和外源化。此外，有选择性地破坏Cd-pericytes，GPR124或Wnt7-β-连环蛋白信号传导显著减少肺ADC的脑和肝转移。我们的发现揭示了一个未被重视的驱动肿瘤转移的细胞和分子范式。版权所有©2023 Elsevier Inc.。保留所有权利。

Brain metastasis of lung cancer causes high mortality, but the exact mechanisms underlying the metastasis remain unclear. Here we report that vascular pericytes derived from CD44+ lung cancer stem cells (CSCs) in lung adenocarcinoma (ADC) potently cause brain metastases through the G-protein-coupled receptor 124 (GPR124)-enhanced trans-endothelial migration (TEM). CD44+ CSCs in perivascular niches generate the majority of vascular pericytes in lung ADC. CSC-derived pericyte-like cells (Cd-pericytes) exhibit remarkable TEM capacity to effectively intravasate into the vessel lumina, survive in the circulation, extravasate into the brain parenchyma, and then de-differentiate into tumorigenic CSCs to form metastases. Cd-pericytes uniquely express GPR124 that activates Wnt7-β-catenin signaling to enhance TEM capacity of Cd-pericytes for intravasation and extravasation, two critical steps during tumor metastasis. Furthermore, selective disruption of Cd-pericytes, GPR124, or the Wnt7-β-catenin signaling markedly reduces brain and liver metastases of lung ADC. Our findings uncover an unappreciated cellular and molecular paradigm driving tumor metastasis.Copyright © 2023 Elsevier Inc. All rights reserved.