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Cancer Res. 2018 Apr 15;78(8):2052-2064. doi: 10.1158/0008-5472.CAN-17-2994. Epub 2018 Mar 22.

Targeting Brain-Adaptive Cancer Stem Cells Prohibits Brain Metastatic Colonization of Triple-Negative Breast Cancer.

Ren D#1,2, Zhu X#1, Kong R#1,3, Zhao Z1,4, Sheng J1, Wang J1,5, Xu X1, Liu J1,6, Cui K1, Zhang XH7, Zhao H8, Wong STC8,7,9.

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Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, Texas.
Outpatient Center, PLA NO.85 Hospital, Shanghai, P.R. China.
Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, P.R. China.
Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, P.R. China.
Department of Orthopedics, Tongji Hospital, Wuhan, P.R. China.
Department of Pharmacy, Changhai Hospital, Shanghai, P.R. China.
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, Texas.
Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas.
Contributed equally


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.

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