Stmc-37. s100a4 is a critical regulator of stemness and the mesenchymal phenotype in gbms

Accumulating evidence indicates that cellular stresses such as chemotherapy, radiation treatment, or hypoxic and acidic microenvironments can either select for or induce cellular changes that confer GBM cells with more stem cell-like or mesenchymal phenotypes. The mesenchymal phenotype is associated with aggressiveness and tumor recurrence in GBMs and stemness in other tumors. In addition, hypoxia and acidosis have been shown to increase the number of tumor initiating cells (TICs) in human GBM cultures, suggesting that elucidating mechanisms that regulate stemness and mesenchymal transition is critical for improving GBM treatment and care. Here we report that S100A4 is a critical regulator of stemness and the mesenchymal phenotype in GBMs. First, we show that S100a4 is a novel marker and a critical regulator of GBM TICs. Using mouse models and patient derived GBM tumorspheres, we show that S100a4 expression is enriched in TICs and that S100a4 function is critical for self-renewal of these cells. Furthermore, selective ablation of S100a4+ cells murine gliomas in vivo is sufficient to block tumor growth. Second, we show that human GBM tumorspheres cultured in low pH induce S100A4 expression and acquire the mesenchymal phenotype. Interestingly, S100A4 knockdown suppresses expression of key epithelial-mesenchymal transition (EMT) regulators, such as SNAIL2, ZEB1, and TGFb1. Importantly, acidosis-induced mesenchymal phenotype requires S100A4 function. Consistently, S100A4 expressi...

Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Chow, K.-h., Park, H. J., George, J., Gallup, A., Wood, S., Yamamoto, K., Neilson, E., Graber, J., Steindler, D., Yun, K. Tags: STEM CELLS Source Type: research