SMAD4 and colorectal carcinoma: For CRC modeling, human small intestinal stem cell organoid cultures were modified using clustered regularly interspersed short palindromic repeat (CRISPR)/CRISPR-associated protein 9 genome editing (Cas9) system to introduce four defined CRC driver mutations (KRASG12D, loss of APC, P53, and SMAD4) (Matano et al., 2015; Drost et al., 2015).