2. Academic Validation
  3. CD44+ lung cancer stem cell-derived pericyte-like cells cause brain metastases through GPR124-enhanced trans-endothelial migration

CD44+ lung cancer stem cell-derived pericyte-like cells cause brain metastases through GPR124-enhanced trans-endothelial migration

  • Cancer Cell. 2023 Aug 9;S1535-6108(23)00252-0. doi: 10.1016/j.ccell.2023.07.012.
Qian Huang 1,  Liping Liu 2,  Dakai Xiao 2,  Zhi Huang 1,  Wenjun Wang 2,  Kui Zhai 1,  Xiaoguang Fang 1,  Jongmyung Kim 3,  James Liu 3,  Wenhua Liang 2,  Jianxing He 4,  Shideng Bao 5
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 2 Department of Thoracic Surgery, the First Affiliated Hospital of Guangzhou Medical University, the State Key Laboratory of Respiratory Disease, and the National Clinical Research Centre for Respiratory Disease, Guangzhou 510120, China.
  • 3 Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
  • 4 Department of Thoracic Surgery, the First Affiliated Hospital of Guangzhou Medical University, the State Key Laboratory of Respiratory Disease, and the National Clinical Research Centre for Respiratory Disease, Guangzhou 510120, China. Electronic address: drjianxing.he@gmail.com.
  • 5 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cancer Stem Cell Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: baos@ccf.org.
PMID: 37595587 DOI: 10.1016/j.ccell.2023.07.012
Abstract

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.

Keywords

Brain metastasis; Cancer stem cells; Extravasation; GPR124; Intravasation; Lung cancer; Trans-endothelial migration; Vascular pericytes.

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