CD44+ Lung Cancer Stem Cell-derived Vascular Pericytes Cause Brain Metastases through GPR124-mediated Trans-endothelial Migration [I]
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-ß-Catenin 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-ß-Catenin signaling markedly reduced brain and liver metastases of lung ADC. Our findings uncover an unappreciated cellular and molecular paradigm driving tumor metastasis. Overall design: Lung adenocarcinoma cell derived pericytes were transduced with non-targeting shRNA or shRNA targeting GPR124 genes. The gene expressions were analized by high throughput RNA sequencing.