Abstract 2522: S100A4 is a critical regulator of stemness and the mesenchymal phenotype in GBMs

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Abstract Glioblastoma (GBM) is one of the most incurable human cancers, and the mesenchymal subtype of GBMs has the worst prognosis. The mesenchymal phenotype and glioma stem cells (GSCs) are associated with tumor recurrence and therapy resistance. While growing evidence suggests that tumor microenvironment modulates stemness and the mesenchymal phenotype, little is known about how these phenotypes are coordinately regulated. 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 regulator of GBM TICs. Using genetically engineered mice 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, we demonstrate that selective ablation of S100a4+ cells in vivo is sufficient to block tumor growth. Second, we show that S100A4 regulates expression of EMT regulators, SNAIL2 and ZEB1, in addition to master transcriptional regulators of the mesenchymal signature genes (CEBPB/D, RUNX1, FOSL2, and BHLHE40), suggesting that S100A4 is an upstream (master) regulator of mesenchymal transition in GBMs. Third, we show that acidosis, a common environmental stress in malignant tumors, induces S100A4 and epithelial-mesenchymal transition (EMT) regulator expression. Importantly, S100A4 is required for acidosis-induced EMT and mesenchymal transition. Consistently, S100A4 expression is strongly associated with the mesenchymal subtype of GBMs, and S100A4 is an independent prognostic indicator for the mesenchymal subtype GBM patient survival. In summary, we show that S100A4 is a critical node in the molecular network that controls glioma stem cells and the mesenchymal phenotype, and propose that targeting S100A4 may simultaneously suppress mesenchymal transition and stemness of glioma cells, particularly in stressful tumor environments. Citation Format: KIn-Hoe Chow, Hee Jung Park, Joshy George, Andrew D. Gallup, Eric Neilson, Kyuson Yun. S100A4 is a critical regulator of stemness and the mesenchymal phenotype in GBMs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2522.