Whereas the MES II cluster again identified hypoxia and stress-related genes like Hmox1, Tnc, Gdf15, and Hspa9, MES II marker genes also included Fosl1, Met, Ccn4, Grb10, and Sema3c, genes that have previously been associated with stemness, tumor cell plasticity and invasion, the regulation of EMT-like processes, and generally an increased tumor aggressiveness59–63. Here, CCN4 is linked to neoplasm.