Targeting brain-adaptive cancer stem cells prohibits brain metastatic colonization of triple-negative breast cancer

Ding Ren, Xiaoping Zhu, Ren Kong, Zhen Zhao, Jianting Sheng, Jiang Wang, Xiaoyun Xu, Jiyong Liu, Kemi Cui, Xiang H.F. Zhang, Hong Zhao, Stephen T. Wong

Research output: Contribution to journalArticle

24 Scopus citations

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)-PLCb-Ca2þ-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.

Original languageEnglish (US)
Pages (from-to)2052-2064
Number of pages13
JournalCancer research
Volume78
Issue number8
DOIs
StatePublished - Apr 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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