Expression Profiling of the MAP Kinase Phosphatase Family Reveals a Role for DUSP1 in the Glioblastoma Stem Cell Niche

AbstractThe dual specificity phosphatases (DUSPs) constitute a family of stress-induced enzymes that provide feedback inhibition on mitogen-activated protein kinases (MAPKs) critical in key aspects of oncogenic signaling. While described in other tumor types, the landscape of DUSP mRNA expression in glioblastoma (GB) remains largely unexplored. Interrogation of the REpository for Molecular BRAin Neoplasia DaTa (REMBRANDT) revealed induction (DUSP4, DUSP6), repression (DUSP2, DUSP7 –9), or mixed (DUSP1, DUSP5, DUSP10, DUSP15)DUSP transcription of select DUSPs in bulk tumor specimens. To resolve features specific to the tumor microenvironment, we searched the Ivy Glioblastoma Atlas Project (Ivy GAP) repository, which highlightDUSP1,DUSP5, andDUSP6 as the predominant family members induced within pseudopalisading and perinecrotic regions. The inducibility ofDUSP1 in response to hypoxia, dexamethasone, or the chemotherapeutic agent camptothecin was confirmed in GB cell lines and tumor-derived stem cells (TSCs). Moreover, we show that loss ofDUSP1 expression is a characteristic of TSCs and correlates with expression of tumor stem cell markersin situ (ABCG2, PROM1, L1CAM, NANOG, SOX2). This work reveals a dynamic pattern of DUSP expression within the tumor microenvironment that reflects the cumulative effects of factors including regional ischemia, chemotherapeutic exposure among others. Moreover, our observation regardingDUSP1 dysregulation within the stem cell niche argue for i...
Source: Cancer Microenvironment - Category: Cancer & Oncology Source Type: research