Abstract
Brain metastases (BM) result from the spread of primary tumors to the brain and are a leading cause of cancer mortality in adults. Secondary tissue colonization remains the main bottleneck in metastatic development, yet this "premetastatic" stage of the metastatic cascade, when primary tumor cells cross the blood-brain barrier and seed the brain before initiating a secondary tumor, remains poorly characterized. Current studies rely on specimens from fully developed macrometastases to identify therapeutic options in cancer treatment, overlooking the potentially more treatable "premetastatic" phase when colonizing cancer cells could be targeted before they initiate the secondary brain tumor. Here we use our established brain metastasis initiating cell (BMIC) models and gene expression analyses to characterize premetastasis in human lung-to-BM. Premetastatic BMIC engaged invasive and epithelial developmental mechanisms while simultaneously impeding proliferation and apoptosis. We identified the dopamine agonist apomorphine to be a potential premetastasis-targeting drug. In vivo treatment with apomorphine prevented BM formation, potentially by targeting premetastasis-associated genes KIF16B, SEPW1, and TESK2 Low expression of these genes was associated with poor survival of patients with lung adenocarcinoma. These results illuminate the cellular and molecular dynamics of premetastasis, which is subclinical and currently impossible to identify or interrogate in human patients with BM. These data present several novel therapeutic targets and associated pathways to prevent BM initiation.Significance: These findings unveil molecular features of the premetastatic stage of lung-to-brain metastases and offer a potential therapeutic strategy to prevent brain metastases. Cancer Res; 78(17); 5124-34. ©2018 AACR.
Highlights
Metastases to the brain (BM) are the most common neoplasm to affect the adult central nervous system, occurring in up to 40% of patients with cancer and at a rate 10 times greater than that of primary neural neoplasms [1]
Through Connectivity Map analysis (CMAP) of these BMIT genes and preliminary in vivo validation, we demonstrated that the dopamine agonist apomorphine inhibited Brain metastases (BM) development in vivo, presumably by inhibiting the premetastatic state
We utilized early-passage BM cell lines derived from primary patient samples of lung-to-BM in our work, as these samples are enriched for brain metastasis initiating cell (BMIC) that have already successfully completed the metastatic process
Summary
Metastases to the brain (BM) are the most common neoplasm to affect the adult central nervous system, occurring in up to 40% of patients with cancer and at a rate 10 times greater than that of primary neural neoplasms [1]. Survival of patients with BM is limited to mere weeks, extended to months upon administration of multimodal treatment [2]. Despite the devastating clinical outcomes, the genetic and molecular events that govern metastatic development remain frustratingly difficult to predict. The process of metastasis is both complicated and extremely inefficient, where only a minute percentage of disseminated tumor cells are capable of surviving the lymphovascular system to establish metastatic tumors. Metastatic cells must first adapt to and seed this. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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