CD44+ Lung Cancer Stem Cell-derived Vascular Pericytes Cause Brain Metastases through GPR124-mediated Trans-endothelial Migration [II]

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-β-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-β-Catenin signaling markedly reduced brain and liver metastases of lung ADC. Our findings uncover an unappreciated cellular and molecular paradigm driving tumor metastasis. Surgical specimens of lung ADC were dissociated with the Papain Dissociation System. The isolated cells were cultured in neurobasal medium. CD44+ CSCs were sorted through FACS sorting according to CD44 expression. The Cd-pericytes were isolated from CD44+ CSCs cultured in pericyte-specific medium. The CSCs de-differentiated from Cd-pericyte were isolated from Cd-pericytes cultured in neurobasal medium for several generations.