Knockout of genes in organogenesis signaling pathways such as TGFβ-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, TGFB1 is linked to cancer.