Brain microenvironment-induced reduction in microRNAs to promote metastatic tumor growth, drug resistance, and survival.

Abstract

e22030 Background: Brain metastases remain a serious obstacle that negatively impacts cancer patient survival. Most deaths due to cancer result from the progressive growth of metastatic, drug-resistant lesions. Moreover, the incidence of brain metastases is rising as a result of an aging population, superior imaging modalities, earlier cancer detection and more effective treatment of systemic disease. Methods: To investigate the role of the brain microenvironment in metastasis, tumor cells were co-cultured with astrocytes - the most abundant normal cell type in the metastatic brain tumor niche. This led to increased tumor cell viability, proliferation and chemoresistance. Microarray-based profiling was then performed to address the effect of the brain microenvironment on miRNA expression levels in tumor cells. Results: Profiling revealed that astrocyte co-culture reduced miRNAs-768-3p, 886-5p and 200c in tumor cells. Inhibition of miRNA-768-3p increased KRas expression, and a specific binding site was identified in the KRas 3’UTR and validated using a luciferase construct. miRNA-768-3p levels were reduced in patient-derived brain metastases relative to normal adult brain. Additionally, miRNA-768-3p was also lower in brain metastases compared to the primary tumors in matched paired samples. Our data demonstrates that the brain microenvironment modulates miRNA-768-3p in metastatic lesions to enhance KRas-mediated tumor survival and promote metastasis. Conclusions: The brain microenvironment regulates the expression of individual miRNAs in tumor cells to promote growth, survival and drug resistance. The brain microenvironment down-regulates the level of certain miRNAs to promote oncogenic signaling and tumor growth while our studies indicate that chemically-engineered miRNA mimics can restore the loss-of-function to reduce the viability of cancer cells. miRNA replacement therapy is a promising and novel therapeutic concept that could save thousands of patients from ineffective treatment, improve patient quality-of-life, overall survival and reduce the devastating impact of brain metastases on the healthcare system.