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While several molecular players and pathways involved in the regulation of a dormant phenotype have been identified ( 4– 6), our understanding of dormancy is still very limited, particularly when it comes to cancer dormancy in the brain ( 7). Therefore, cancer cell dormancy may be of a particular interest in the context of brain metastases. Brain metastases tend to develop late in the course of progressive metastatic disease, and thus tend to have a longer latency period as compared to metastases at other sites ( 3). Brain metastases develop in ~20% of cancer patients and are associated with a very poor prognosis ( 1, 2). Evidence suggests that non-proliferating, asymptomatic cancer cells that lay dormant in different organs since their initial dissemination may be responsible for metastatic relapse. The vast majority of breast cancer deaths are due to metastases, which often develop years after the initial diagnosis of the primary tumor. Our study identified mechanisms that could be targeted to induce/maintain cancer dormancy and thereby prevent metastatic relapse. Dormant cancer cells were further characterized by a reduced expression of glycolysis genes in vivo, and inhibition of glycolysis in vitro resulted in a reversible growth arrest reminiscent of dormancy. BGN expression was significantly downregulated in patient brain metastases as compared to the matched primary breast tumors and BGN overexpression in cancer cells inhibited their growth in vitro and in vivo.

BGN gene, encoding a small proteoglycan biglycan, was strongly upregulated in dormant cancer cells in vivo. We used an in vivo model of triple negative breast cancer brain metastasis to identify differences in transcriptional profiles between dormant and proliferating cancer cells in the brain. 3Experimental Cancer Genetics, Wellcome Sanger Institute, Hinxton, United KingdomĮxit of quiescent disseminated cancer cells from dormancy is thought to be responsible for metastatic relapse and a better understanding of dormancy could pave the way for novel therapeutic approaches.2School of Medicine, Medical Science and Nutrition, University of Aberdeen, Aberdeen, United Kingdom.1School of Medicine, University of Leeds, Leeds, United Kingdom.Ashley Sunderland 1, Jennifer Williams 1, Tereza Andreou 1†, Nora Rippaus 1, Christopher Fife 1, Fiona James 1, Yolanda Dyah Kartika 1, Valerie Speirs 2, Ian Carr 1, Alastair Droop 3 and Mihaela Lorger 1*

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