To study the role of SMAD4 in CRC progressiontoward metastatic competency, we adopted a CRC tumor progression organoid(TPO) model (Figure 1A).4 This model was developed to mimicthe adenoma-to-carcinoma progression in CRC by the sequential introductionof mutations in four frequently mutated oncogenes (APC (A), KRAS (K), P53 (P), and SMAD4 (S)) by CRISPR/Cas9 in human colon organoids derivedfrom human-derived healthy colon epithelium, providing an excellentisogenic organoid model to study the role of SMAD4 inactivation oncancer progression in advanced CRC on a molecular level. The gene discussed is APC; the disease is carcinoma.