CD44+ Lung Cancer Stem Cell-derived Pericyte-like Cells Cause Brain Metastases through GPR124-mediated Trans-endothelial Migration

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 GPR124-mediated trans-endothelial migration (TEM). CD44+ CSCs in the perivascular niche generate the majority of vascular pericytes in lung ADC. CSC-derived pericyte-like cells (Cd-pericytes) exhibit remarkable TEM capacity to effectively intravasate into vessel lumina, survive in the circulation, extravasate into the brain parenchyma, and then de-differentiate into tumorigenic CSCs to form metastases. Moreover, Cd-pericytes uniquely express GPR124, a G-protein-coupled receptor. GPR124 mediates through Wnt7-CTNNB1 activation 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 Wnt7-CTNNB1 signaling markedly reduced brain and liver metastases of lung ADC. Our findings uncover an unappreciated cellular and molecular paradigm driving tumor metastasis.

肺癌脑转移致死率极高，但其具体转移机制至今仍未明确。本研究发现，肺腺癌（lung adenocarcinoma, ADC）中源自CD44+肺癌干细胞（cancer stem cells, CSCs）的血管周细胞，可通过GPR124介导的跨内皮迁移（trans-endothelial migration, TEM）强力诱发脑转移。肺腺癌血管微环境中的CD44+肺癌干细胞，可产生肺腺癌中绝大多数的血管周细胞。由肺癌干细胞分化而来的周细胞样细胞（CSC-derived pericyte-like cells, Cd-pericytes）具备极强的跨内皮迁移能力，可有效侵入血管腔、在血液循环中存活、外渗进入脑实质，随后去分化为致瘤性肺癌干细胞以形成转移灶。此外，Cd-pericytes特异性表达GPR124，一种G蛋白偶联受体。GPR124通过激活Wnt7-CTNNB1信号通路，增强Cd-pericytes的跨内皮迁移能力，从而促进肿瘤转移过程中的内渗与外渗这两个关键步骤。进一步研究表明，选择性阻断Cd-pericytes、GPR124或Wnt7-CTNNB1信号通路，可显著抑制肺腺癌的脑转移与肝转移。本研究揭示了一条此前未被认知的、驱动肿瘤转移的细胞与分子机制范式。