4 years ago

JAK2-binding long noncoding RNA promotes breast cancer brain metastasis.

Jianwei Zhou, Liuqing Yang, Ping Li, Lingegowda Selanere Mangala, Jian Song, Dihua Yu, Yan Zhou, Chunlai Li, Elsa R Flores, Gary E Gallick, Mien-Chie Hung, David H Hawke, Peter K Park, Wenhao Yang, Ke Liang, Anil K Sood, Gabriel Lopez-Berestein, Qingsong Hu, Shouyu Wang, Suyun Huang, Jun Yao, Yuedong Yang, Weiya Xia, Chunru Lin, Jeffrey R Marks
Conventional therapies for breast cancer brain metastases (BCBMs) have been largely ineffective because of chemoresistance and impermeability of the blood-brain barrier. A comprehensive understanding of the underlying mechanism that allows breast cancer cells to infiltrate the brain is necessary to circumvent treatment resistance of BCBMs. Here, we determined that expression of a long noncoding RNA (lncRNA) that we have named lncRNA associated with BCBM (Lnc-BM) is prognostic of the progression of brain metastasis in breast cancer patients. In preclinical murine models, elevated Lnc-BM expression drove BCBM, while depletion of Lnc-BM with nanoparticle-encapsulated siRNAs effectively treated BCBM. Lnc-BM increased JAK2 kinase activity to mediate oncostatin M- and IL-6-triggered STAT3 phosphorylation. In breast cancer cells, Lnc-BM promoted STAT3-dependent expression of ICAM1 and CCL2, which mediated vascular co-option and recruitment of macrophages in the brain, respectively. Recruited macrophages in turn produced oncostatin M and IL-6, thereby further activating the Lnc-BM/JAK2/STAT3 pathway and enhancing BCBM. Collectively, our results show that Lnc-BM and JAK2 promote BCBMs by mediating communication between breast cancer cells and the brain microenvironment. Moreover, these results suggest targeting Lnc-BM as a potential strategy for fighting this difficult disease.

Publisher URL: http://doi.org/10.1172/JCI91553

DOI: 10.1172/JCI91553

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