APC and colorectal carcinoma: Matano and colleagues model human colon adenocarcinoma by introducing canonical colorectal cancer (CRC) driver mutations into primary human colon organoid cultures (Matano et al., 2015), revealing that mutations in APC, SMAD4, TP53, and KRAS simultaneously are sufficient to model colonic adenomas but not tumorigenesis, perhaps due to the lack of TME components within the organoids.