1. Targeting Brain-Adaptive Cancer Stem Cells Prohibits Brain Metastatic Colonization of Triple-Negative Breast Cancer
- Author
-
Xiaoping Zhu, Jianting Sheng, Zhen Zhao, Ren Kong, Kemi Cui, Hong Zhao, Xiaoyun Xu, Jiyong Liu, Ding Ren, Jiang Wang, Stephen T. C. Wong, and Xiang Zhang
- Subjects
0301 basic medicine ,Cancer Research ,Cell ,Phospholipase C beta ,Triple Negative Breast Neoplasms ,Mice, SCID ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Mice, Inbred NOD ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Animals ,Humans ,S100 Calcium-Binding Protein A4 ,RNA, Messenger ,Enzyme Inhibitors ,Triple-negative breast cancer ,Cell Proliferation ,Retrospective Studies ,Brain Neoplasms ,business.industry ,Phospholipid Ethers ,Cancer ,Cadherins ,medicine.disease ,Adaptation, Physiological ,Metastatic breast cancer ,Protocadherins ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Cancer research ,Calcium ,Female ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,business ,Signal Transduction ,Edelfosine ,Brain metastasis - Abstract
Triple-negative breast cancer (TNBC) exhibits more traits possessed by cancer stem cells (CSC) than other breast cancer subtypes and is more likely to develop brain metastases. TNBC patients usually have shorter survival time after diagnosis of brain metastasis, suggesting an innate ability of TNBC tumor cells in adapting to the brain. In this study, we establish novel animal models to investigate early tumor adaptation in brain metastases by introducing both patient-derived and cell line–derived CSC-enriched brain metastasis tumorsphere cells into mice. We discovered astrocyte-involved tumor activation of protocadherin 7 (PCDH7)-PLCβ-Ca2+-CaMKII/S100A4 signaling as a mediator of brain metastatic tumor outgrowth. We further identified and evaluated the efficacy of a known drug, the selective PLC inhibitor edelfosine, in suppressing the PCDH7 signaling pathway to prohibit brain metastases in the animal models. The results of this study reveal a novel signaling pathway for brain metastases in TNBC and indicate a promising strategy of metastatic breast cancer prevention and treatment by targeting organ-adaptive cancer stem cells. Significance: These findings identify a compound to block adaptive signaling between cancer stem cells and brain astrocytes. Cancer Res; 78(8); 2052–64. ©2018 AACR.
- Published
- 2018