Knockout of genes in organogenesis signaling pathways such as TGFb-SMAD specifically leads to a growth advantage of 3D spheroids while inactivation of epigenetic modifiers (Bcor, Kmt2d, METTL3 and METTL14) in monolayer and 3D spheroids results in opposite fitness outcomes, and these genes often function as tumor suppressors in human cancer. Here, KMT2D is linked to neoplasm.