We performed CRISPR screens on both a sub-library and a genome-wide scale in human intestinal organoids to discover cancer driver genes. We investigated the Wnt and the TGFB pathway and used both WT, APC-mutant and APC-TP53-mutant organoids. Overall design: To investigate how the identified SWI/SNF screening hits confer TGFB resistance, we assessed changes in binding of SMAD3 to the chromatin upon ARID1A or SMARCA4 perturbation and TGFB treatment