Targeting Neuronal-like Metabolism of Metastatic Tumor Cells as a Novel Therapy for Breast Cancer Brain Metastasis
[Technical Report, Final Report]
University of Notre Dame
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Metastasis is the cause of 90 of all cancer-related deaths with 30 of breast cancer-associated fatalities being attributable to brain metastasis. In this project, we hypothesize that the transcriptome reprogramming of tumor cells through interactions with brain astrocytes reshape metastatic tumor cell metabolism. Here, we report that brain microenvironment epigenetically upregulates glutamate decarboxylase 1 GAD1 in the tumor cell, a regulator of the GABA neurotransmitter glutamate metabolic pathway, which is critical for brain metastatic outgrowth. Using cell-based co-culture and in vivo brain metastasis imaging models, we found that downregulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. Most importantly, targeting GABA metabolic pathway using a BBB permeable FDA-approved antiseizure drug vigabatrin decreased the incidence of brain metastasis in vivo. Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth.
- Medicine and Medical Research
- Anatomy and Physiology