Dysregulated mitogen ‐activated protein kinase signalling as an oncogenic basis for clear cell sarcoma of the kidney

Abstract The oncogenic mechanisms and tumour biology underpinning Clear Cell Sarcoma of Kidney (CCSK), the second commonest paediatric renal malignancy, are poorly understood and currently therapy depends heavily on doxorubicin with cardiotoxic side‐effects. Previously, we characterised the balanced t(10;17)(q22;p13) chromosomal translocation, identified at that time as the only recurrent genetic aberration in CCSK. This translocation results in an in‐frame fusion of the genes YWHAE (encoding 14‐3‐3ε)and NUTM2, with a somatic incidence of 12%. Clinico‐pathological features of that cohort suggested that this aberration might be associated with higher stage and grade disease. Since no primary CCSK cell line exists, we generated various stably transfected cell lines containing doxycycline‐inducible HA‐tagged‐YWHAE‐NUTM2, in order to study the effect of expressing this transcript. 14‐3‐3ε‐NUTM2‐expressing cells exhibited significantly greater cell migration compared to isogenic controls. Gene and protein expression studies were indicative of dysregulated MAPK‐/PI3K‐AKT‐signalling, and by blocking these pathways using neutralising antibodies, the migratory advantage conferred by the transcript was abrogated. Importantly, CCSK tumour samples similarly show upregulation/ activation of these pathways. These results support the oncogenic role of 14‐3‐3ε‐NUTM2 in CCSK and provide avenues for the exploration of novel therapeutic approaches.
Source: The Journal of Pathology - Category: Pathology Authors: Tags: Original Paper Source Type: research