CS-04 * STAT3 INVOLVEMENT IN AN EMT-LIKE PROCESS IN GLIOBLASTOMA BRAIN TUMOR INITIATING CELLS

Abstract

Glioblastoma Multiforme (GBM) is the most aggressive subtype of brain tumour with a median survival of 15 months. Currently, GBM is managed by a combination of maximal safe resection followed by radiation and chemotherapy. However, GBM invariably recurs, highlighting the need to better delineate the basis of recurrent disease and develop novel more effective and targeted therapies. The Signal Transducer and Activator of Transcription 3 (STAT3) is abnormally active in GBM. A growing body of evidence supports the hypothesis that STAT3 is a major oncogenic molecular hub in patient-derived Brain Tumor Initiating Cells (BTICs) leading to stemness, proliferation, invasion and therapeutic resistance. Recently, there has been an increasing awareness that Epithelial to Mesenchymal Transition (EMT) is an essential process promoting the generation of highly tumorigenic cells with stem-like characteristics. The mesenchymal GBM profile, characterized by significantly shortened progression-free and overall survival, suggests that an EMT-like process has clinical relevance in GBM. Moreover, recent studies support a possible role for STAT3 in an EMT-like process in GBM. Here we show in that SLUG (encoded by SNAI2) appears to be expressed at higher levels than other EMT regulators in patient samples and matching BTICs. High SLUG protein level is observed in a large number of BTIC lines and positively correlates with activated STAT3. Moreover, SLUG is significantly decreased after pharmacological inhibition of STAT3 signalling using a well-characterized STAT3 inhibitor (Stattic) and a novel clinically relevant JAK2 inhibitor. Furthermore, IL-6 treatment or overexpression of a constitutively active form of STAT3 promote SLUG expression. SLUG and the subsequent EMT-like process may play an important role in the aggressive mesenchymal phenotype of GBM and the archetypal characteristics of BTICs: self-renewal, invasion, tumorigenicity and therapeutic resistance. We propose that STAT3-dependent EMT-like process and the key regulator SLUG are interesting novel therapeutic targets in GBM.