Brachyury Is Associated with Glioma Differentiation and Response to Temozolomide

Abstract

Glioblastomas (GBMs) are the most aggressive tumor type of the central nervous system, mainly due to their high invasiveness and innate resistance to radiotherapy and chemotherapy, with temozolomide (TMZ) being the current standard therapy. Recently, brachyury was described as a novel tumor suppressor gene in gliomas, and its loss was associated with increased gliomagenesis. Here, we aimed to explore the role of brachyury as a suppressor of glioma invasion, stem cell features, and resistance to TMZ. Using gene-edited glioma cells to overexpress brachyury, we found that brachyury-positive cells exhibit reduced invasive and migratory capabilities and stem cell features. Importantly, these brachyury-expressing cells have increased expression of differentiation markers, which corroborates the results from human glioma samples and in vivo tumors. Glioma cells treated with retinoic acid increased the differentiation status with concomitant increased expression of brachyury. We then selected TMZ-resistant (SNB-19) and TMZ-responsive (A172 and U373) cell lines to evaluate the role of brachyury in the response to TMZ treatment. We observed that both exogenous and endogenous brachyury activation, through overexpression and retinoic acid treatment, are associated with TMZ sensitization in glioma-resistant cell lines. In this study, we demonstrate that brachyury expression can impair aggressive glioma features associated with treatment resistance. Finally, we provide the first evidence that brachyury can be a potential therapeutic target in GBM patients who do not respond to conventional chemotherapeutic drugs.